AU2007265965A1

AU2007265965A1 - Pyridylisoxazole derivative

Info

Publication number: AU2007265965A1
Application number: AU2007265965A
Authority: AU
Inventors: Hajime Asano; Koichi Hasumi; Jun-Ya Kato; Yasuhiro Matsumoto; Shuji Ohta; Mami Okada; Takahisa Saito; Jun Sato; Shuichiro Sato; Kazuhiko Shirota; Hiroyuki Suzuki
Original assignee: Aska Pharmaceutical Co Ltd
Current assignee: Aska Pharmaceutical Co Ltd
Priority date: 2006-06-28
Filing date: 2007-06-26
Publication date: 2008-01-03
Anticipated expiration: 2027-06-26
Also published as: US8207203B2; AU2007265965B2; JP5244591B2; WO2008001930A1; CA2656159C; KR101412943B1; EP2036905B1; US20090306145A1; EP2036905A4; CA2656159A1; ES2396251T3; EP2036905A1; JPWO2008001930A1; CN101472921B; CN101472921A; KR20090024273A

Description

1 DESCRIPTION Pyridylisoxazole Derivatives 5 Technical Field This invention relates to novel pyridylisoxazole derivatives or salts thereof, methods of their preparation and their use. Compounds of this invention exhibit p38MAPkinase inhibiting action and in consequence inhibitory action to the production of tumor 10 necrosis factor-a (TNF-a), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), cyclooxygenase-II (COXII) and the like. They are, therefore, useful as the treating agent of TNF-a-related diseases, IL-1-related diseases, IL-6-related diseases, IL-8-related diseases and COX-II-related diseases and the like. 15 Background Art TNF-c, IL-1, IL-6, IL-8 and COX-II are mainly the proteins (cytokines) produced by immunocompetent cells such as macrophage and neutrophil, which are known as one of the important factors 20 participating in, besides immunomodulatory function and inflammatory symptoms, the hematopoietic system, endocrine system, nervous system and the like. On the other hand, p38MAPkinase has the action of activating transcription factors such as NF-KB, AP-1 and CREB. These 25 transcription factors bind to the DNA sequence common among TNF-c, IL-1, IL-6, IL-8, COXII and the like to promote transcription of mRNA which synthesizes the respective cytokines. p38MAPkinase, therefore, has the action to promote the production of cytokines such as TNF-a. While the transcribed mRNA is 30 inactivated upon binding to specific protein and then quickly degraded, p38MAPkinase has an action to dissociate the bonds between mRNA and the specific proteins. In this respect also p38MAPkinase is deemed to contribute to the production of cytokines such as TNF-a. 35 Accordingly, inhibition of p38MAPkinase leads to inhibition of 2 the production of cytokines such as TNF-a and, therefore, is expected to be useful for the treatment or prophylaxis of the diseases related to the cytokines such as TNF-a, for example, acute inflammation, chronic inflammation, rheumatoid arthritis, osteoarthritis, gout, 5 inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastritis, colonic polyposis, large bowel cancer, colon cancer, asthma, bronchitis, bronchial asthma, allergic rhinitis, ARDS, chronic obstructive pulmonary disease, pulmonary fibrosis, congestive heart disease, ischemic heart disease, myocardial infarction, arteriosclerosis, 10 hypertension, angina, Alzheimer's disease, reperfusion injury, angiitis, cerebrovascular disease, meningitis, multiple sclerosis, osteoporosis, bony sclerosis, Behcet's Syndrome, bone metastasis, multiple myeloma, acute infectious disease, septic shock, sepsis, toxic-shock syndrome, tuberculosis, DIC, psoriasis, atopic dermatitis, cirrhosis, 15 renal fibrosis, cachexia, AIDS, cancer, autoimmune disease, diabetes, Castleman's disease, mesangial nephritis, endometriosis and preterm delivery. In the past, as the compounds having p38MAPkinase inhibiting action, for example, imidazole derivatives (cf. Bioorganic & 20 Medicinal Chemistry, Vol. 5, No. 1, 49 - 64 (1997) and JP Tokuhyo Hei 7(1995)-503017), pyrazole derivatives (cf. PCT International Publications W098/52940 Pamphlet and WOOO/39116 Pamphlet) and isoxazole derivatives (cf. JP Tokuhyo Hei 11(1999)-503722, JP2002-179656A, PCT International Publication W02004/17968 25 Pamphlet, JP 2000-86657A and PCT International Publication W02004/22555 Pamphlet) have been proposed. However, these compounds are subject to such problems that most of them exhibit side effects and have not matured as marketable medicines. Only recently certain kind of triazine derivatives were found to 30 possess potent p38MAPkinase-inhibiting action and high speed metabolism, and hence were expected to show reduced side effects and to be prospective antirheumatic medicine (cf. J. Med. Chem., Vol. 47, 6283-6291 (2004)). 35 Disclosure of the Invention 3 An object of the present invention is to provide pyridyl isoxazole derivatives which exhibit excellent p38MAPkinase inhibiting activity and reduced side effects. We have now discovered that a certain kind of novel 5 4-(4-pyridyl)isoxazole derivatives possess excellent p38MAPkinase-inhibiting activity and high expiration rate of metabolically active substance in blood, and hence have the potential to reduce the side effects which have been the drawback in past p38MAPkinase-inhibitors, and completed the present invention. 10 Thus, according to the invention, pyridylisoxazole derivatives which are represented by a formula (I) R4 O R~~ N Y-R 5 15 R

R

3 N in the formula,

R

1 and R 2 each independently stands for hydrogen, halogen, 20 lower alkyl, lower alkoxy, amino, lower alkylamino, di-lower alkyl amino, phenyl-lower alkylamino, acylamino, lower alkylthio or lower alkylsulfinyl,

R

3 stands for naphthyl, optionally lower alkyl-substituted heteroaryl or a group represented by the following formula (A) 25 X1 I (A) X~X 3 30 wherein X1, X 2 and X 3 each independently stands for hydrogen, halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, hydroxyl, lower alkanoyl, lower haloalkanoyl or phenyl; or X' and X 2 together stand for lower alkylenedioxy group,

R

4 stands for hydrogen or lower alkyl, 4

R

5 stands for phenyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, which may be optionally substituted with 1 - 3 substituents selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, hydroxyl, lower alkanoyl, 5 lower haloalkanoyl, lower alkylthiocarbonyl, lower haloalkylthio carbonyl, amino, lower alkylamino, di-lower alkylamino and nitro, Y stands for -(CH 2 )n-, -CO-, -CH(CH 3 )-, -C(CH 3

)

2 -, -0-, -NH- or C-_ ,wherein n is an integer of 1 - 3, with the proviso that, where both of R1 and R 2 stand for hydrogen and 10 R 3 stands for the group of the formula (A) and two of X1, X 2 and X 3 stand for hydrogen, the remaining one of X1, X 2 and X 3 is a group other than hydrogen atom or halogen atom, or pharmaceutically acceptable salts thereof are provided. The invention also provides p38MAPkinase inhibitors 15 characterized by containing pyridylisoxazole derivatives of the formula (I) or pharmaceutically acceptable salts thereof. In the present specification, the term, "lower" signifies that a group modified by this term contains no more than 6, preferably no more than 4, carbon atoms. 20 "Lower alkyl" can be of straight chain or branched chain, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl; methyl, ethyl, n-propyl, isopropyl and n-butyl being preferred among these. "Lower alkoxy" includes oxy (0) group bound to the lower alkyl, such as, for 25 example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutyloxy, sec-butyloxy, n-pentyloxy and n-hexyloxy; methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy being preferred among these. "Lower alkanoyl" includes carbonyl (C=0) group bound to the lower alkyl, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, 30 isovaleryl and pivaloyl; acetyl and propionyl being preferred among these. Furthermore, "halogen" and "halo" include fluorine, chlorine, bromine and iodine; fluorine, chlorine and bromine being particularly preferred.

5 "Lower alkylamino" in the definition of R 1 signifies amino group (-NH 2 ) of which one of the hydrogen atoms is substituted with the lower alkyl; and "di-lower alkylamino", amino group of which two hydrogen atoms are substituted with the lower alkyl. Here the two 5 lower alkyl groups in such di-lower alkylamino may be the same or different. "Phenyl-lower alkylamino" in the definition of R1 is such a lower alkylamino of which lower alkyl moiety is substituted with phenyl, examples of which include benzylamino, 2-phenylethylamino, 3-phenyl-n-propylamino, 4-phenyl-n-butylamino, 1-phenylethylamino 10 and 1-(phenylmethyl)ethylamino; benzylamino and 2-phenylethyl amino being preferred among these. "Acylamino" in the definition of R' signifies acylated amino, examples of the acyl group including lower alkanoyl groups such as formyl, acetyl, propionyl and butyryl, and aroyl groups such as 15 benzoyl; acetyl and benzoyl being preferred among these. "Lower alkylthio" and "lower alkylsulfinyl" in the definition of R' respectively mean thio (S) group and sulfinyl (SO) group, to which the lower alkyl is bound. "Optionally lower alkyl-substituted heteroaryl" in the 20 definition of R 3 signfies unsubstituted or the lower alkyl-substituted monocyclic or polycyclic heteroaryl groups, wherein the heteroaryl groups include 5- to 10-membered aromatic groups having in the ring 1 - 3 hetero atoms selected from N, 0 and S, specific examples of which include furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, 25 isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolyl, isoquinolyl and quinazolyl; furyl, pyrrolyl, thienyl and pyridyl being preferred among these. 30 In the groups represented by the following formula x( A ) 2I (A) 5X3 35 6 in the definition of R 3 , X1, X 2 and X 3 may substitute at any of the different positions on the benzene ring, and their binding sites are subject to no particular limitation. "Lower haloalkyl" in the definition of X1, X 2 and X 3 in the 5 above formula (A) includes lower alkyl groups as earlier defined, which are substituted with one or more same or different halogen atoms, examples of which incude fluoromethyl, trifluoromethyl, 1,2-dichloroethyl, 1-chloro-2-bromoethyl, pentafluoroethyl, 1-chloro-n-propyl, 2-bromo-2-methylethyl, 3-chloro-n-pentyl, 10 2-bromo-3-chloro-n-hexyl and the like. Of these, C 1

-

2 lower alkyl substituted with 1 - 5 same or different halogen atoms are preferred. "Lower haloalkoxy" in the definition of X', X 2 and X 3 in the above formula (A) includes oxy (0) group to which above lower haloalkyl is bound. In particular, C 1

-

2 lower haloalkoxy groups 15 substituted with 1 - 5 same or different halogen atoms are preferred. "Lower haloalkanoyl" in the definition of X', X 2 and X 3 in the formula (A) includes aforesaid lower alkanoyl groups which are substituted with 1 or more halogen atoms, examples of which include fluoroacetyl, chloroacetyl, bromoacetyl, trifluoroacetyl, 20 3-fluoropropionyl, 3-chloropropionyl, 3-bromopropionyl, 4-chlorobutyryl and the like. Of these, fluoroacetyl, trifluoroacetyl, 3-fluoropropionyl and 3-chloropropionyl are preferred. As examples of "lower alkylenedioxy" in the definition of X1, X 2 and X 3 in the formula (A), methylenedioxy, ethylenedioxy, 25 trimethylenedioxy and the like can be named, among which methylenedioxy and ethylenedioxy are preferred. As examples of "lower haloalkyl", "lower alkanoyl" and "lower haloalkanoyl" in the definition of R 5 , respectively those groups named as for "lower haloalkyl" "lower alkanoyl" and "lower haloalkanoyl" in 30 the definition of X', X 2 and X 3 in the formula (A) can be named, among which the preferred groups also are the same. "Lower alkylthiocarbonyl" in the definition of R 5 signifies thiocarbonyl (C=S) to which aforesaid lower alkyl is bound, examples of which include thioacetyl, thiopropionyl, thiobutyryl, thiopentanoyl, 7 thiohexanoyl and the like, thioacetyl and thiopropionyl being preferred among these. "Lower haloalkylthiocarbonyl" in the definition of R 5 signifies above lower alkylthiocarbonyl which is substituted with 1 or more 5 halogen atoms, examples of which include fluorothioacetyl, chlorothioacetyl, bromothioacetyl, trifluorothioacetyl, chlorothio propionyl, chlorothiobutyryl, bromothiopentanoyl, fluorothiohexanoyl and the like, fluorothioacetyl, chlorothioacetyl, bromothioacetyl and trifluorothioacetyl being preferred among these. 10 Where both RI and R 2 in the formula (I) are hydrogen, R 3 stands for the group of formula (A) and two of XI, X 2 and X 3 stand for hydrogen, the compounds in which the remaining one of X1, X 2 and X 3 stands for hydrogen or halogen are disclosed in JP 2000-86657A and hence are excluded from the compounds of the formula (I) of the 15 present invention. A preferred group of compounds in the present invention are those of the formula (I) in which R1 and R 2 each independently stands for hydrogen, amino, lower alkylamino or di-lower alkylamino, in particular, those of the formula (I) in which both RI and R 2 stand for 20 hydrogen. When either one of RI and R 2 stands for hydrogen and the other stands for a group other than hydrogen, that group preferably is substituted at 2-position of the pyrimidine ring. Another preferred group of compounds in the present invention are those of the formula (I) in which R 2 stands for a group 25 represented by the following formula 11 ,,( A) 2 XX 30 in particular, those in which XI, X 2 and X 3 each independently stands for hydrogen, halogen, lower alkyl or lower alkoxy. Still another preferred group of compounds in the present invention are those of the formula (I) in which R 4 stands for hydrogen. 35 A further preferred group of compounds in the present 8 invention are those of the formula (I) in which R 5 stands for phenyl which is optionally substituted with 1 - 3 substituents selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, hydroxyl, lower alkanoyl, lower haloalkanoyl, lower alkylthiocarbonyl, lower 5 haloalkylthiocarbonyl, amino, lower alkylamino, di-lower alkylamino and nitro. In particular, those compounds of the formula (I) in which

R

5 stands for phenyl which is optionally substituted with 1 or 2 substituents selected from halogen and lower alkyl are better preferred, inter alia, the compounds of the formula (I) in which R 5 is 10 phenyl, 2-halophenyl, 2,6-dihalophenyl, 2-lower alkylphenyl, 3-lower alkylphenyl or 2,5-di-lower alkylphenyl are best preferred. Another preferred group of compounds in the present invention are the compounds of the formula (I) in which Y stands for -CH2- or -(CH2)2-. 15 Particularly preferred compounds according to the invention are as follows: 3-(3-methylphenyl)-5-(3-phenylpropionylamino)-4-(4-pyridyl) isoxazole, 3-(3-methylphenyl)-5-[(2-methylphenyl)propionylamino]-4 20 (4-pyridyl)isoxazole, 5-[(3-chlorophenyl)propionylaminol-3-(2-fluoro-5-methyl phenyl)-4-(4-pyridyl)isoxazole, 3-(4-fluoro-3-methylphenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole, 25 5-[(2-chlorophenyl)acetylamino]-3-(4-fluoro-3-methylphenyl)-4 (4-pyridyl)isoxazole, and 3-(4-fluoro-3-methylphenyl)-5-(3-phenylpropionylamino)-4 (4-pyridyl)isoxazole. Also as the typical examples of the compounds of the formula 30 (I) offered by the present invention, the following can be named other than those given in the later appearing Examples: 3-(4-fluorophenyl)-4-[4-(2-methylaminopyridyl)]-5 phenylacetylaminoisoxazole, 3-(4-fluorophenyl)-4-[4-(2-methylaminopyridyl)]-5-(3 35 phenylpropionylamino)isoxazole, 9 4- [4-(2-benzylaminopyridyl)] -3- (4-fluorophenyl)-5 -phenyl acetylaminoisoxazole, 4- [4-(2-benzylaminopyridyl)] -3-(4-fluorophenyl)-5-(3-phenyl propionylamino)isoxazole, 5 4- [4-(2-acetylaminopyridyl)] -3-(4-fluorophenyl)-5-phenyl acetylaminoisoxazole, 4- [4-(2-acetylaminopyridyl)] -3-(4-fluorophenyl)-5-(3-phenyl propionylamino)isoxazole, 4- [4-(2-benzoylaminopyridyl)] -3-(4-fluorophenyl)-5-phenyl 10 acetylaminoisoxazole, 4- [4-(2-benzoylaminopyridyl)] -3-(4-fluorophenyl)-5-(3-phenyl propionylamino)isoxazole, 3-(4-fluoro-3-methylphenyl)-5-(N-methyl-phenylacetylamino) 4-(4-pyridyl)isoxazole, 15 3-(4-fluoro-3-methylphenyl) -5- [N-methyl-(3-phenylpropionyl) amino] -4-(4-pyridyl)isoxazole, 5- [(2-aminophenyl)acetylamino] -3-(4-fluoro-3-methylphenyl) 4-(4-pyridyl)isoxazole, 3-(4-fluoro-3-methylphenyl) -5- [(2-hydroxyphenyl) 20 acetylaminol-4-(4-pyridyl)isoxazole, 3,4-di(4-pyridyl)-5-phenylacetylaminoisoxazole, 3,4-di(4-pyridyl)-5-(3-phenylpropionylamino)isoxazole, 3- [4-(2-methylpyridyl)] -5-phenylacetylamino-4-(4-pyridyl) isoxazole, 25 3- [4-(2-methylpyridyl)] -5-(3-phenylpropionylamino)-4-(4 pyridyl)isoxazole, and the like. The compounds of the formula (I) of the present invention can also be present in the form of salt. As examples of the salts, those with inorganic acids such as hydrochloric acid, hydrobromic acid, 30 sulfuric acid, nitric acid, phosphoric acid and the like; and those with organic acids such as acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid, p-toluenesulfonic acid and the like can be name. Of these, pharmaceutically acceptable salts are preferred. The compounds of the formula (I) according to the invention 35 can be prepared, for example, by the following method (a) or (b).

10 Method (a): A compound of the formula (I) in which R 4 stands for hydrogen, i.e., a compound of the following formula, 5 0 1 9HN-"-Y-R5 R O2 X0

R

3 N 10 in the formula, R1, R 2 , R 3 , RI and Y have the previously given significations, can be prepared by reaction of a compound represented by the following formula, 15 R1

NH

2 R2 --- ,1 /0

R

3 N 20 in the formula, R1, R 2 and R 3 have the previously given significations, with a carboxylic acid compound of the following formula, 25 0 Y-R5 H-0- 1 1 -Y-R~ in the formula, R 5 and Y have the previously given significations, 30 or its reactive derivative (for example, acid halide, acid anhydride, mixed acid anhydride, active amide, active ester or the like). Method (b): A compound of the formula (I) in which R 4 stands for a lower alkyl, i.e., a compound represented by the following formula, 35 11 R 0 1R N-(Y-R5 R ( I-2 R- O R 3 N 5 in the formula, R', R 2 , R 3 , R 5 and Y have the previously given significations, and R stands for a lower alkyl, can be prepared by N-lower alkylation of a compound of the formula (I-1). 10 In the method (a), it is desirable that the carboxylic acid compound of the formula (III) is advancedly treated with, for example, 1,1-carbonyldiimidazole (CDI), 1,1-thionyldiimidazole or the like, to be converted to a reactive derivative thereof such as active amide. It is also possible when acid halide, for example, acid chloride, is used as 15 the reactive derivative of the carboxylic acid compound of the formula (III), to treat the acid halide in advance with, for example, imidazole and DBU or the like to convert it to other reactive derivative such as imidazolide. Furthermore, when R1 in the compounds of the formula (II) 20 represents amino, lower alkylamino or phenyl-loweralkylamino, it is advantageous to protect the amino, lower alkylamino or phenyl-lower alkylamino in advance with a suitable protective group, for example, with the use of di-tert-butyl dicarbonate (BOC), acetonyl acetone, benzyloxycarbonyl chloride (Z-chloride) or the like where necessary, 25 removing the protective group after termination of the reaction. The reaction of a compound of the formula (II) with a carboxylic acid compound of the formula (III) or a reactive derivative thereof can generally be conducted in inert organic solvent, for example, ethers such as dioxane, tetrahydrofuran and 30 dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; amides such as dimethylformamide and dimethyl acetamide; dimethylsulfoxide; and, where necessary, in the presence of a base, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 35 triethylamine, diisopropylethylamine, pyridine or the like. The 12 suitable reaction temperature is normally within a range of 0*C to the reflux temperature of the reaction mixture, preferably from the temperature under cooling with ice up to 50*C. The carboxylic acid compound of the formula (III) or reactive 5 derivative thereof can be generally used in an amount of at least 1 mol, preferably 1.5 - 10 mols, inter alia, 2 - 5 mols, per mol of the compound of the formula (II). Also the use rate of the base is generally at least 1 mol, preferably 1 - 2 mols, per mol of the carboxylic acid compound of the formula (III) or reactive derivative 10 thereof. Compounds of the formula (1I) which are used as the starting material can be readily synthesized by those synthesis methods known per se, for example, following the route indicated by the following reaction scheme 1. Concerning the particulars of the 15 reaction conditions and the like of the reaction scheme 1, refer to Example 1, a) given later. Reaction scheme 1: X N N N

R

3 N OH 20 R2 in which R1, R 2 and R 3 have the previously given significations, and X stands for halogen. The N-lower alkylation of the compounds of the formula (I-1) 25 according to the method (b) can generally be carried out by reacting the compounds with lower alkyl halide, for example, iodomethane, ethyl bromide, propyl bromide and the like, in inert organic solvent, for example, alcohols such as methanol, ethanol and isopropanol; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; 30 aromatic hydrocarbons such as benzene, toluene and xylene; amides such as dimethylformamide and dimethylacetamide; and dimethylsulfoxide; and in the presence of a suitable base such as 13 sodium hydride, potassium carbonate, pyridine and the like. The suitable reaction temperature is normally within a range of 0*C to the reflux temperature of the reaction mixture, preferably from room temperature to 50*C. 5 The lower alkyl halide can be used generally in an amount of at least 1 mol, preferably 1.1 - 5 mols, inter alia, 1.2 - 4 mols, per mol of a compound of the formula (I-1). The use rate of the base is generally at least 1 mol, preferably within a range of 1 - 5 mols, per mol of a compound of the formula (I-1). 10 Those compounds of the formula (I) of the present invention which are prepared following the above-described methods can be isolated and purified by the means known per se, for example, recrystallization, column chromatography, thin-layer chromatography and the like. 15 The pyridylisoxazole derivatives represented by the formula (I) of the present invention or their pharmaceutically acceptable salts possess excellent p38MAPkinase-inhibiting action with reduced side effects, and are useful for the treatment or prophylaxis of human and 20 other mammals' TNF-a-, IL-1-, IL-6-, IL-8- and COX-II-related diseases, for example, acute inflammation, chronic inflammation, rheumatoid arthritis, osteoarthritis, gout, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastritis, colonic polyposis, large bowel cancer, colon cancer, asthma, bronchitis, bronchial asthma, 25 allergic rhinitis, ARDS, chronic obstructive pulmonary disease, pulmonary fibrosis, congestive heart disease, ischemic heart disease, myocardial infarction, arteriosclerosis, hypertension, angina, Alzheimer's disease, reperfusion injury, angiitis, cerebrovascular disease, meningitis, multiple sclerosis, osteoporosis, bony sclerosis, 30 Behcet's Syndrome, bone metastasis, multiple myeloma, acute infectious disease, septic shock, sepsis, toxic-shock syndrome, tuberculosis, DIC, psoriasis, atopic dermatitis, cirrhosis, renal fibrosis, cachexia, AIDS, cancer, autoimmune disease, diabetes, Castleman's disease, mesangial nephritis, endometriosis and preterm delivery.

14 The TNF-a production inhibitory action based on the p38MAPkinase- inhibiting action possessed by the compounds of the formula (I) of the present invention and metabolic expiration rate in blood of the compounds of the formula (I) of the present invention can 5 be demonstrated by the following experiments. (1) Measurement of TNF-ca production-inhibiting action THP-1, human-derived culture cells (purchased from Dainippon Pharmaceutical Co.), was suspended (1 x 105 cells/mL) in RPMI 1640 medium (10% fetal bovine serum, containing 100 10 units/mL of penicillin). The THP-1 cell suspension 1.6 mL was inoculated in a 24-well culture plate, to which further a solution of test substance as dissolved in RPMI 1640 medium to make the final concentration of the test substance 100 nM and 0.2 mL of LPS (E. coli 055: B5-derived, dissolved in RPMI 1640 medium, Difco) of 10 pg/mL 15 in concentration were added, followed by 2 hours' culture under the conditions of 37*C and 5% CO 2 . The supernatant which was obtained upon centrifuge (500 x g, 5 minutes) was measured with ELISA (Amersham Biosciences, TNF-a Human, ELISA Biotrak System) to quantize TNF-a. The TNF-a production inhibition rate 20 (%) at 100 nM of each test substance was calculated according to the following formula, quantity of TNF-ca when each test substance was used 1 1- quantity of TNF- a in control experiment x 100 The results are shown in the later-appearing Table A. 25 (2) Measurement of the compounds' metabolic rate: Each test compound was added to potassium phosphate buffer (50 mmol/L, pH7.4) containing NADPH generating system (comprising 3.3 mmol/L MgCl2, 3.3 mmol/L glucose 6-phosphate, 1.3 mmol/L P-NADP+ and 0.4 unit/mL glucose 6-phosphate 30 dehydrogenase) (in which occasion the final concentration was rendered 1 pimol/L) and incubated at 37*C for 2 minutes. After the incubation, a suspension of human liver S9 (the supernatant fraction obtained by centrifuging comminuted human liver cell fluid at 9000 x g) in potassium phosphate buffer was added to the system, to the final 15 concentration of 0.5 mg protein/mL. This reaction mixture was incubated at 37*C for 5 minutes, and to which 4 volume times the reaction mixture of acetonitrile was added, mixed, cooled with ice and centrifuged (2000 x g, 10 minutes). A part of the supernatant was 5 taken and analyzed by LC/MS/MS, to determine the remaining rate of unchanged substance in the reaction solution. The results are shown in the following Table A, concurrently with the measured results of TNF-a production-inhibiting action in (1) above.

16 TABLE A TNF-x generation- Metabolic rate Compound Structural formula inhibiting action (remaining ratio of (inhibition: unchanged rate: %, 100 nM) substance: %) N' H N Example 103 'o 6 5. 5 1 7. 6 Me -1 N N H N Example 106 'o \5 2. 9 23 . 3 Me N me N HN Example 12, ,o0 5 8. 1 5 0. 5 Me, N F C NHN Example 123 ,o 7 8. 1 5 8. 0 Me N F 0 MeN F HN Examplel124 Me 0O ci 8 5. 2 5 9. 7 F 0 NN Example 125 o 6 6. 0 20. 1 Me - N

F

17 Thus the pyridylisoxazole derivatives represented by the formula (I) of the present invention or their pharmaceutically acceptable salts can be orally or parenterally (e.g., intramuscular injection, intravenous injection, intrarectal or percutaneous 5 administration and the like) administered to patients who need the therapy, treatment or prophylaxis as medicines for therapy, treatment or prophylaxis of human or other mammals' diseases, as p38MAPkinase inhibitor having excellent activity and high metabolic rate. 10 Where the compounds of the present invention are used as medicines, they can be formulated into certain preparation forms according to their utility, with non-toxic excipients, such as solids (e.g., tablet, hard capsule, soft capsule, granule, powder, grain, pill, troche and the like); semi-solids (e.g., suppository, ointment and the like) or 15 liquid (e.g., injection, emulsion, suspension, lotion, spray and the like). As the non-toxic excipients useful for such preparations, for example, starch, gelatine, glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methyl cellulose, carboxymelyi cellulose or salts thereof, gum arabic, polyethylene glycol, alkyl 20 p-hydroxybenzoate, syrup, ethanol, propylene glycol, petrolatum, carbowax, glycerine, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like can be named. The preparations can also contain other therapeutically useful medicines. Thus, according to the present invention, pharmaceutical 25 compositions containing effective amount of the pyridylisoxazole derivatives represented by the formula (I) or pharmaceutically acceptable salts thereof, concurrently with non-toxic excipients are provided. While the content of a compound of the present invention in 30 such preparations or compositions differs according to the preparation form, in general terms it is desirable to be within a range of 0.1 - 50% by weight for solid and semi-solid forms, and within a range of 0.05 10% by weight for liquid forms. The administration dosage of a compound of the present 35 invention is variable over a wide range according to the species, age, 18 body weight, administration route, seriousness of symptoms and doctor's diagnosis, of the patients including human and other warm-blooded animals. Whereas, in general terms, it can range 0.02 - 20 mg/kg, preferably 0.2 -8 mg/kg, per day. Obviously, dosages 5 less than the lower limit or more than the upper limit of the above-specified range may be administered depending on seriousness of the patient's symptoms, doctor's diagnosis and the like. The dosage can be administered as a single dose or plural divided doses per day. 10 Examples Hereinafter the present invention is explained in further details, referring to Examples and Preparation Examples. 15 Example 1 3-(2,3-Difluorophenvl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole a) 5 -Amino-3- (2, 3-difluorophenyl) -4- (4-pyridyl)isoxazole In 15 mL of methanol, 2.31 g of 28% sodium methoxide methanol solution was dissolved, and a suspension of 0.93 g of 20 4-pyridylacetonitrile hydrochloride in 10 mL of THF was added, followed by an hour's stirring at room temperature. Then a solution of 1.15 g of 2,3-difluorobenzhydroxymoyl chloride in 5 mL of methanol was added dropwise, followed by 20 hours' stirring at room temperature. The reaction solution was extracted with ethyl acetate 25 after addition of water. The ethyl acetate extract was washed with brine, dried over anhydrous magnesium sulfate, and removed of the solvent by reduced pressure distillation. The resultant residue was purified on 100 g silica gel column chromatography (eluent, ethyl acetate -+ ethyl acetate: methanol = 9:1) to provide 1.06 g (yield: 65%) 30 of the title compound as pale yellow crystal. 1H-NMR(CDCl 3 )5:8.51(dd,J=1.7Hz,4.4Hz,2H),7.31-7.21(m,2H), 7.19-7.13(m, 1H),7.00(dd,J=1.7Hz,4.4Hz,2H), 4.94(bs,2H) 35 Mass,m/e:273(M*),63(base) 19 b) 3-(2,3-Difluorophenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole In 3 mL of THF, 68 mg of imidazole and 152 mg of DBU were 5 dissolved, into which 155 mg of phenylacetyl chloride was dropped under cooling with ice and stirring, followed by 1.5 hours' stirring at room temperature. Then a solution of 137 mg of 5-amino-3-(2,3 difluorophenyl)-4-(4-pyridyl)isoxazole and 152 mg of DBU in 3 mL of THF was added dropwise, followed by 26 hours' stirring at room 10 temperature. After addition of water, the reaction solution was extracted with ethyl acetate. The ethyl acetate extract was washed first with saturated aqueous NaHCO 3 solution and then with brine, dried over anhydrous magnesium sulfate, and removed of the solvent by reduced pressure distillation. The resultant residue was purified 15 by thin-layer silica gel chromatography (developer, hexane: ethyl acetate = 1:1) to provide 88 mg (yield: 45%) of the title compound as colorless crystal. 1H-NMR(CDCl 3 )8:8.43(dd,J=1.6Hz,4.5Hz,2H),7.78(bs, 1H), 20 7.43-7.13(m,8H),6.81(dd,J=1.6Hz,4.5Hz,2H),3.78(s,2H) Mass,m/e:39 1(M+),9 1 (base) Example 2 5-[2-(2-chlorophenyl)acetylaminol-3-(2,3-difluorophenyl)-4 25 (4-pyridvl)isoxazole To a solution of 0.171 g of 2'-chlorophenylacetic acid in 5 mL of THF, 0.162 g of CDI was added, and stirred at room temperature for 1.5 hours. Then a solution of 0.152 g of DBU and 0.137 g of 5-amino-3- (2,3-difluorophenyl)-4-(4-pyridyl)isoxazole in 1 mL of THF 30 was added, and stirred at room temperature for 18 hours. Afte addition of water, the reaction solution was extracted with ethyl acetate. The ethyl acetate extract was washed first with saturated aqueous NaHCO3 solution and then with brine, dried over anhydrous magnesium sulfate, and removed of the solvent by reduced pressure 35 distillation. The resultant residue was purified on 3 g silica gel 20 column chromatography (eluent, ethyl acetate) to provide 0.126 g (yield, 59%) of the title compound as pale yellow crystal. 1H-NMR(CDCl 3 )6:8.45(dd,J=1.5Hz,4.4Hz,2H),7.83(bs, 1H), 5 7.47-7.43(m,1H),7.36-7.12(m,6H),6.91(dd,J=1.5Hz,4.4Hz,2H), 3.89(s,2H) Mass,m/e:425(M+), 125(base) In the following, the compounds of Examples 3-183 were 10 synthesized in the manner similar to Examples 1 and 2. Example 3 3-(2,3-Difluorophenyl)-5-(phenylpropionylamino)-4-(4-pyridyl) isoxazole 15 1H-NMR(CDCl 3 )6:8.41(dd,J=1.5Hz,4.6Hz,2H),8.02(bs,1H), 7.32-7.13(m,8H),6.87(dd,J=1.5Hz,4.6Hz,2H), 3.01(t,J=7.3Hz,2H),2.77(t,J=7.3Hz,2H) Mass,m/e:405(M+),9 1(base) 20 Example 4 3-(2,4-Difluorophenyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole a) 5-Amino- 3-(2,4- difluorophenyl- 4- (4-pyridyl)isoxazole 25 IH-NMR(CDCls)6:8.50(dd,J=1.5Hz,4.6Hz,2H), 7.52-7.45(m, 1H),7.00-6.96(m,3H),6.87-6.80(m,1H), 4.93(bs,2H) Mass,m/e:273(M+),63(base) 30 b) 3-(2,4-Difluorophenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 1H-NMR(CDC1 3 )6:8.43(dd,J=1.5Hz,4.6Hz,2H),7.50-7.34(m,4H), 7.30-7.25(m,2H),7.00-6.94(m,lH),6.83-6.77(m,3H),3.77(s,2H) 35 Mass,m/e:391(M+),91(base) 21 Example 5 5-[2-(2-Chlorophenyl)acetylamino]-3-(2,4-difluorophenyl)-4 (4-pyridyl)isoxazole 5 1H-NMR(DMSO-d6)8:11.24(bs, 1H),8.49(dd,J=1.6Hz,4.5Hz,2H), 7.68-7.61(m, 1H),7.46-7.36(m,3H), 7.33-7.24(m,3H), 7.09(dd,J=1.6Hz,4.5Hz,2H),3.91(s,2H) Mass,m/e:425(M+), 125(base) 10 Example 6 3-(2,4-Difluorophenvl)-5-(phenylpropionylamino)-4-(4-pyridyl) isoxazole 15 1H-NMR(CDCl 3 )6:8.45(dd,J=1.6Hz,4.5Hz,2H),7.76(bs,iH), 7.50-7.43(m,1H),7.33-7.17(m,5H),7.01-6.95(m,1H), 6.88(dd,J=1.6Hz,4.5Hz,2H),6.84-6.78(m,1H), 3.01(t,J=7.4Hz,2H),2.77(t,J=7.4Hz,2H) Mass,m/e:405(M+),9 1 (base) 20 Example 7 5-[(2-Chlorophenyl)propionylamino]-3-(2,4-difluorophenyl)-4 (4-pyridyl)isoxazole 25 1H-NMR(CDCl 3 )6:8.42(d,J=6.lHz,2H),8.26(bs,1H), 7.49-7.43(m,1H),7.35-7.31(m,1H),7.24-7.15(m,3H), 6.99-6.94(m,1H),6.91(d,J=6.lHz,2H),6.82-6.77(m,1H), 3.11(t,J=7.6Hz,2H),2.78(t,J=7.6Hz,2H) Mass,m/e:439(M+),273(base) 30 Example 8 5-[(3-Chlorophenyl)propionvlaminol-3-(2,4-difluorophenyl)-4 (4-pyridyl)isoxazole 35 1H-NMR(CDCl 3 )8:8.44(bs,1H),8.39(d,J=5.8Hz,2H), 22 7.48-7.43(m, 1H), 7.21-7. 18(m,3H),7.08-7.06(m, 1H), 6.99-6.94(m, 1H),6.88(d,J=6.OHz,2H),6.82-6.77(m, 1H), 2.98(t,J=7.OHz,2H), 2.77(t,J=7.OHz,2H) Mass, m/e:439(M+) , 273(base) 5 Example 9 3-(2,4-Difluorop~henvl)-5- [(2-methylphenvl)propionylamino] -4 (4-pyridyl)isoxazole 10 1H-NMR(CDCl)8:8.40(d,J=5.9Hz,2H),8.22(bs, iH), 7.49-7.43(m, 1H),7. 157. 10(m,4H),6.99-6.94(m, 1H), 6.89(d,J=5.9Hz,2H),6.82-6.77(m, 1H),3.0(t,J=7.6Hz, 2H), 2. 72(t,J=7.6Hz, 2H), 2.28(s, 3H) Mass, m/e:419(MI), 105(base) 15 Example 10 3- (2.4-Difluorophenyl) 5-[(3-methvlphenyl)propionylaminol -4 (4-pyridyl)isoxazole 20 IH-NMR(CDCl 3 )5:8.43(dd,J=1 .7Hz,4.5Hz,2H), 7.83(bs, iH), 7.49-7.43(m, 1H),,7. 11-7.06(m,4H),6.99-6.95(m, iH), 6.87(dd,J=1.7Hz,4.5Hz,2H),6.83-6.77(m, 1H), 2.96(t,J=7.2Hz,2H),2.74(t,J=7.2Hz,2H),2.32(s,3H) Mass, m/e:419(MI), 105(base) 25 Example 11 3- (2. 6-Difluorophenyl) -5 -(phenylacetylamino) -4-(4-pvridyl)isoxazole a) 5 -Amino-3 -(2,6- difluorop henyl) -4- (4 -pridyl)isoxazole 30 'H-NMR(CDCl 3 )6:8.48(dd,J=1 .5Hz,4.6Hz,2H),7.47-7.39(m, 1H), 7.00-6.95(m,4H),4.97(bs,2H) Mass, m/e:273(M+), 63(base) b) 3- (2. 6-Difluorophenyl)>5-(phenylacetylamino)-4-(4-pyridyl) 35 isoxazole 23 IH-NMR(CDC1 3 )5:8.42(dd,J=1 .5Hz,4. 7Hz,2H),7.45-7.37(m,5H), 7.3 1-7.29(m, 2H),6.98&6.92(m,2H),6.8 1(dd,J=i .5Hz,4.6Hz,2H), 3.79(s,2H) 5 Mass, m/e: 39 1(M+),9 I(base) Example 12 5- [2-(2- Chlorophenvl)acetylamino -3-(2. 6difluorophenyl)-4 (4-pyridyl)isoxazole 10 1H-NMR(CDC1 3 ):8.43(dd,J=1 .5Hz,4.4Hz,2H), 7.79(bs, iH), 7.47-7.30(m, 5H),6.97-6.93(m,2H),6.9 1(dc,J=1.5Hz,4.4Hz,2H), 3.90(s,2H) Mass, m/e:425(MI), 125(base) 15 Example 13 3- (3,4- Difluorophenyl) -5- (phenyvlacetylamino) -4-(4-pyridyl)isoxazole a) 5-Amino- 3-(3, 4-ifluorophenyl) -4(4-pridl)isoxazole 20 1H-NMR(DMSO-d 6 )5:8.44(dd,J=1.2Hz,4.8Hz,2H), 7.54-7.36(m,2H), 7.32(bs,2H),7. 19-7. 13(m, 1H), 7.05(dd,J=1.2Hz,4.8Hz,2H) Mass, m/e:273 (M+), 63 (base) 25 b) 3-(3, 4Difluorophenyl) 5-(phenylacetylamino)-4- (4-pyridyl) isoxazole IH-NMR(DMSO-d 6 )5: 11 .09(bs, 1H),8.47(dd,J=1.3Hz,4.8Hz,2H), 7.56-7.45(m,2H),7.36-7.23(m,5H), 7.22-7. 17(m, 1H), 30 7.07(dd,J=1.3Hz,4.8Hz,2H),3.67(s,2H) Mass, m/e: 39 1 (MI),9 1 (base) Example 14 5- [2- (2- Chlorophenyl)acetylaminol -3- (3, 4-difluorophenyl) -4 35 (4-pyridyl)isoxazole 24 1H-NMR(DMSO-d)S: 11. 14(bs, 1H),8.54(dd,J=1.5Hz,4.4Hz,2H), 7.51-7.18(m,7H),7.18(dd,J=1.5Hz,4.4Hz,2H),3.87(s,2H) Mass,m/e:391 (M+),9 1(base) 5 Example 15 3-(3-Chloro-2-fluorophenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole a) 5-Amino-3-(3-chloro-2-fluorophenyl)-4-(4-pyridyl)isoxazole 10 lH-NMR(DMSO-d 6 )S:8.40(dd,J=1.5Hz,4.5Hz,2H), 7.78-7.73(m,1H),7.48-7.44(m,3H),7.36(td,J=0.8Hz,7.9Hz,iH), 6.98(dd,J=1.5Hz,4.5Hz,2H) Mass,m/e:289(M+),63(base) 15 b) 3-(3-Chloro-2-fluorophenyl)-5-(phenylacetylamino)-4-(4 pyridvl)isoxazole IH-NMR(CDC1 3 )S:8.43(dd,J=1.7Hz,4.4Hz,2H),7.78(bs, 1H), 20 7.53-7.48(m,1H),7.43-7.32(m,5H),7.30-7.28(m,1H), 7.17(td,J=1.2Hz,7.9Hz,1H),6.80(dd,J=1.7Hz,4.4Hz,2H), 3.78(s,2H) Mass, m/e:407(M+),91 (base) 25 Example 16 5-[(2-Chlorophenyl)acetylamino]-3-(3-chloro-2-fluorophenvl)-4 (4-pyridyl)isoxazole 1H-NMR(DMSO-d 6 )S:11.28(bs, 1H),8.49(dd,J=1.6Hz,4.5Hz,2H), 30 7.82-7.76(m, 1H),7.55-7.50(m, 1H),7.47-7.36(m,3H), 7.34-7.29(m,2H),7. 10(dd,J=1.6Hz,4.5Hz,2H),3.91(s,2H) Mass,m/e:441(M+), 125(base) Example 17 25 3-(3-Chloro-2-fluorophenyl)- 5-(phenyipropionviamino) -4- (4-pyridyl) isoxazole 1H-NMR(CDCl 3 )8:8.42(dd,J=1 .5Hz,4.6Hz,2H), 5 8.O(bs, 1H),7.547.49(m, 1H), 7.37-7.27(m,3H), 7.25-7. 15(m,4H),6.86(dd,J=1.5Hz,4.6Hz,2H), 3.02(t,J=7.4Hz, 2H),2. 78(t,J=7.4Hz, 2H) Mass,m/e:42 1 (M+),9 1(base) 10 Example 18 3-(4-Chloro-2-fluorophenvl)-5(phenlacetlamilo)-4(4-pridl) isoxazole a) 5 -Amino- 3- (4-chloro-2fluorophenyl) -4- (4-pyridyl)isoxazole 15 1H-NR(DMSOd 6 )58.40(d,J5.4Hz,2H), 7.53-7.5 1(m,2H),7.43(m,3H),6.98(d,J=5.4Hz,2H) Mass, m/e:289 (M+), 63 (base) b) 3-(4- Chloro-2-luorophenvl) -5-(phenylacetylamino) -4 20 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )5:8.43(dd,J=1.5Hz,4.6Hz,2H), 7.66(bs, 1H),7.43-7.35(m,4H), 7.28-7.22(m,3H), 7.07(dd,J=1.9Hz,9.6Hz, 1H),6.79(dd,J=1.5Hz,4.6Hz,2H), 25 3.77(s,2H) Mass, m/e:4O7(M+),9 1 (base) Example 19 5- [(2- Chiorop~henyi) acetylamino] -3- (4-chioro- 2-fluorophenyl) -4 30 (4-Pvrid-vl)isoxazole IH-NMR(DMSO-d 6 )8: 11 .25(bs, 1H),8.49(dd,J=1.5Hz,4.6Hz,2H), 7.62-7.56(m,2H), 748-7.38(m,3H), 7.33-7.28(m,2H), 7. 1(dd,J=1.5Hz,4.6Hz,2H),3.91(s,2H) 35 Mass, m/e44 1(M'), 125(base) 26 Example 20 3-(4-Chloro-2-fluorophenyl)-5-(phenylpropionylamino)-4-(4-pyridyl) isoxazole 5 IH-NMR(CDCl 3 )5:8.44(bs,1H),8.37(d,J=5.5Hz,2H), 7.40(t,J=7.7Hz,1H),7.30-7.17(m,6H), 7.07(dd,J=1.9Hz,9.6Hz, 1H),6.85(d,J=5.5Hz,2H), 3.00(t,J=7.3Hz,2H),2.76(t,J=7.3Hz,2H) 10 Mass,m/e:421(M+),91(base) Example 21 3-(4-Chloro-3-fluorophenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 15 a) 5-Amino- 3 -(4-chloro-3 -fluorophenyl) -4- (4-pyridvl)isoxazole IH-NMR(CDCl 3 )5:8.56(dd,J=1.5Hz,4.2Hz,2H), 7.38(t,J=8.OHz,1H),7.25(dd,J=1.9Hz,9.6Hz,1H), 7.13-7.11(m,1H),7.05(dd,J=1.5Hz,4.2Hz,2H),4.91(bs,2H) 20 Mass,m/e:289(M+),63(base) b) 3-(4-Chloro-3-fluorophenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 25 1H-NMR(DMSO-d 6 )S:11.12(bs,1H),8.48(dd,J=1.7Hz,4.4Hz,2H), 7.68(t,J=8.OHz,1H),7.45(dd,J=1.9Hz,10Hz,1H), 7.35-7.25(m,5H),7.19(dd,J=1.lHz,8.1Hz,1H), 7.08(dd,J=1.7Hz,4.4Hz,2H),3.68(s,2H) Mass,m/e:407(M+),9 1 (base) 30 Example 22 5-[(2-Chlorophenyl)acetylamino]-3-(4-chloro-3-fluorophenyl)-4 (4-pyridyl)isoxazole 35 IH-NMR(DMSO-d6)8:11.17(bs,1H),8.54(dd,J=1.5Hz,4.2Hz,2H), 27 7.68(t,J=8.OHz, 1H), 7.47(dd,J=1.9Hz, 10Hz, 1H), 7.44-7.41(m, 1H),7.38-7.35(m, 1H),7.31-7.29(m,2H), 7.22-7.20(m, 1H),7.19(dd,J=1.5Hz,4.2Hz,2H),3.87(s,2H) Mass,m/e:442(M+), 125(base) 5 Example 23 3-(4-Chloro-3-fluorophenyl)-5-(phenylpropionylamino)-4-(4-pyridyl) isoxazole 10 1H-NMR(DMSO-d 6 )8:10.91(bs,1H),8.52(dd,J=1.5Hz,4.4Hz,2H), 7.68(t,J=8.OHz,1H),7.45(dd,J=1.9Hz,10Hz,1H), 7.30-7.27(m,2H),7.22-7.18(m,4H),7.09(dd,J=1.5Hz,4.4Hz,2H), 2.86(t,J=7.3Hz,2H),2.68(t,J=7.3Hz,2H) Mass,m/e:42 1(M+),9 1(base) 15 Example 24 3-(2-Chloro-4-fluorophenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole a) 5 -Amino-3 -(2-chloro-4-fluorophenyl) -4-(4-pyridyl)isoxazole 20 1H-NMR(DMSO-d 6 )8:8.36(dd,J=1.6Hz,4.5Hz,2H), 7.61-7.56(m,2H),7.37(td,J=2.7Hz,8.5Hz,1H), 6.92(dd,J=1.6Hz,4.5Hz,2H) Mass,m/e:289(M+),63(base) 25 b) 3-(2-Chloro-4-fluorophenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole 'H-NMR(CDCl 3 )8:8.39(dd,J=1.7Hz,4.4Hz,2H),7.84(bs,1H), 30 7.45-7.27.(m,6H),7.14(dd,J=2.8Hz,8.4Hz,1H), 7.08(td,J=2.8Hz,8.4Hz,1H),6.73(dd,J=1.7Hz,4.4Hz,2H), 3.78(s,2H) Mass,m/e:407(M+),9 1(base) 35 Example 25 28 5- K[2- Chlorophenvl) acetylaminol -3- (2-chloro-4-fluorophenyl) -4 (4-pyridvl)isoxazole IH-NMR(CDC1 3 ):8.41(dd,J=1 .5Hz,4.2Hz,2H), 7.89(bs, 1H), 5 7.48-7.29(m,5H),7.15(dd,J=2.5Hz,8.3Hz, 1H), 7.09(td,J=2.5Hz,8.3Hz, 1H),6.84(dd,Jl. 5Hz,4.2Hz, 2H), 3.90(s,2H) Mass,m/e&44 1(M'), 1 25(base) lo Examle 26 3-(2-Chloro-4-fluorophenyl)5(3-phenvlpropionvlamino) -4-(4-pyridyl) isoxazole 1H-NMR(CDC1 3 ):8.39(dd,J=1.7Hz,4.4Hz,2H), 7.99(bs, 1W), 15 7.42(dd,J=5.8Hz,8.5Hz, 1H),7.33-7.27(m,2H),7.24-7. 18(m,3H), 7. 15(dd,J=2.7Hz,8.5Hz, iH), 7. 11-7.06(m, iH), 6.8 1(dd,J=1.7Hz,4.4Hz,2H),3.02(t,J=7.3Hz,2H), 2. 78(t,J=7.3Hz, 2W) Mass,m/e:42 1 (M+),9 1 (base) 20 Example 27 3- (3- Chloro-4-fluorophenyl) 5 (Phenylacetylamino) -4- (4-pyvridvl) isoxazole a) 5 -Amino- 3 -(3-chloro-4-fluorophenyl) -4- (4-pyridyl)isoxazole 25 IH-NMR(DMSO-d 6 )5:8.45(dd,J=1 .6Hz, 4.5Hz, 2H), 7.56(dd,J=2. 1Hz, 7.1Hz, 1H), 7.48(t,J=8.9Hz, 1H), 7.35-7.29(m,3H), 7.05(dd,J=1.6Hz,4.5Hz,2H) Mass, m/e:289(M+), 6 3(base) 30 b) 3- (3-Chloro-4fluorophenv1)-5-(phenylacetylamino) -4- (4-pyridyl) isoxazole* 1H-NMR(DMSO-d 6 )5: 11. 1O(bs, 1H),8.47(dd,J=1.5Hz,4.6Hz,2H), 35 7.62(dd,J=2.5Hz, 7.1Hz, 1H),7.50(t,J=8.9Hz, lB), 29 7.37-7.24(m,6H),7.07(dd,J=1.5Hz,4.6Hz,2H),3.68(s,2H) Mass,m/e:407(M+),9 1 (base) 5 Example 28 5-[2-(2-Chlorophenyl)acetylamino]-3-(3-chloro-4-fluorophenyl)-4 (4-pyridyl)isoxazole H-NMR(DMSO-d)6:11.15(bs,1H),8.54(dd,J=1.5Hz,4.4Hz,2H), 10 7.63(dd,J=2.lHz,7.1Hz,1H),7.50(t,J=8.9Hz,1H), 7.45-7.27(m,5H),7.19(dd,J=1.5Hz,4.4Hz,2H),3.87(s,2H) Mass,m/e:441(M+), 125(base) Example 29 15 3-(3-Bromo-4-fluorophenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole a) 5-Amino-3 -(3-bromo-4-fluorophenyl) -4- (4-pvridyl)isoxazole 1H-NMR(CDC1 3 )5:8.57(dd,J=1.5Hz,4.2Hz,2H), 20 7.72(dd,J=1.9Hz,6.6Hz,1H),7.30-7.26(m,1H), 7.10(t,J=8.5Hz,1H),7.05(dd,J=1.5Hz,4.2Hz,2H), 4.69(bs,2H) Mass,m/e:333(M+),63(base) 25 b) 3-(3-Bromo-4-fluorophenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )6:8.51(dd,J=1.5Hz,4.2Hz,2H), 7.68(dd,J=2.3Hz,6.6Hz,1H),7.50(bs,1H),7.42-7.37(m,3H), 30 7.27-7.18(m,3H),7.07(t,J=8.5Hz,lH), 6.90(dd,J=1.5Hz,4.2Hz,2H),3.76(s,2H) Mass, m/e:45 1(M+),9 1(base) Example 30 30 3-(3-Bromo-4-fluorophenyl)- 5 [2-(2-chlorophenvl)acetylamino] -4 (4-pyridyl)isoxazole IH-NMR(CDC1 3 )5:8.53(dd,J=1 . 5Hz,4.6Hz, 2H), 5 7.69(dd,J=2.3Hz,6.6Hz, 1H),7.54(bs,1IH),7.46-7.43(m, 1H), 7.34-7.29(m,3H),7.2 1-7.20(m, 1H),7.08(t,J=8.5Hz, IH), 6.99(dd,J=1.5Hz,4.6Hz,2H),3.87(s,2H) Mass, m/e:48 7(M+), 1 25(base) 10 Example 31 3-(3-Bromo-4-fluorophenyvl)-5 -[2-(3-methoxyphenyl)acetylamino] 4 (4-pyridyl)isoxazole IH-IN{R(CDCl 3 )6:8.52(dd,J=1 .5Hz,4. 2Hz, 2H), 15 7.67(dd,J=2.3Hz,6.4Hz, 1H),7.53(bs, 1H),7.3 1(t,J=7.7Hz,1H), 7.20-7. 18(m, iH), 7.08(t,J=8.4Hz, iH), 6.90(dd,J=1.5Hz,4.2Hz,3H),6.83(d,J=7.7Hz, 1H),6.78(bs, iH), 3. 80(s, 3H),3.7 2(s, 2H) Mass, m/e:482(M+), 12 1(base) 20 Example 32 3- (3-Bromo-4-fluorophenyl)-5- (3-phenyipropionylamino) -4- (4-pyvridyl) isoxazole 25 1H-NMR(CDC1 3 )5:8.53(dd,J=1 .5Hz,4.6Hz,2H), 7.67(dd,J=1.9Hz,6.6Hz, 1H),7.58(bs, iH), 7.32-7. 17(m,6H), 7.08(t,J=8. 1Hz, 1H),6.96(dd,Jzl .5Hz,4.6Hz,2H), 3.01 (t,J=7.3Hz, 2H),2.75 (t,J=7.3Hz, 2H) Mass, m/e:465(M+),9 1 (base) 30 Example 33 5- (Phenylacetylamino)- 3-(3.4- dichiorop henyi) -4- (4-pvridyl)isoxazole a) 5 -Amino- 3 -(3,4 4dichlorophenvk-4-(4-pvridl)isoxazole 35 IH-NMR(CDCl 3 )6:8.57(dd,J=1 .6Hz,4.5Hz,2H), 31 7.59(d,J=1.9Hz, 1H),7.43(d,J=8.3Hz, 1H), 7.20(dd,J=1.9Hz,8.3Hz, 1H),7.05(dd,J=1.6Hz,4.5Hz,2H), 4.89(bs,2H) Mass,m/e:305(M+),63(base) 5 b) 5-(Phenylacetylamino)-3-(3,4-dichlorophenyl)-4-(4-pyridyl) isoxazole 1H-NMR(CDCl 3 )5:8.51(dd,J=1.5Hz,4.3Hz,2H), 10 7.55(bs,1H),7.54(d,J=2.3Hz,1H),7.42-7.34(m,4H), 7.27-7.24(m,2H),7.11(dd,J=1.9Hz,8.4Hz,iH), 6.90(dd,J=1.6Hz,4.3Hz,2H),3.76(s,2H) Mass,m/e:423(M+),9 1(base) 15 Example 34 5-[(2-Chlorophenyl)acetylaminol-3-(3,4-dichlorophenvi)-4-(4-pyridlyl) isoxazole 1H-NMR(CDC1 3 )S:8.53(dd,J=1.6Hz,4.5Hz,2H), 20 7.70(bs,1H),7.56(d,J=2.1Hz,1H),7.46-7.39(m,2H), 7.35-7.28(m,3H),7.13(dd,J=2.1Hz,8.3Hz,1H), 6.99(dd,J=1.6Hz,4.5Hz,2H),3.87(s,2H) Mass,m/e:457(M+), 125(base) 25 Example 35 3-(3,4-Dichlorophenvl)-5-(3-phenylpropionylamino)-4-(4-pyridyl) isoxazole IH-NMR(DMSO-d 6 )S:8.53(dd,J=1.5Hz,4.4Hz,2H), 30 7.72(d,J=8.lHz,1H),7.65(d,J=1.9Hz,1H),7.33-7.25(m,3H), 7.24-7.18(m,3H),7.10(dd,J=1.5Hz,4.4Hz,2H), 2.86(t,J=7.3Hz,2H),2.68(t,J=7.3Hz,2H) Mass, m/e:437(M+),9 1 (base) 35 Example 36 32 5- [(2-chlorophenyl)acetylaminol -3-(2,6-dichlorophenyl)-4-(4-pyridyl) isozazole a) 5-Amino- 3- (2,6-dichlorophenyl) -4- (4-pyridyl)isoxazole 5 IH-NMR(DMSO-d)8:8.36(dd,J=1.9Hz,4.6Hz,2H), 7.64-7.54(m,5H),6.90(dd,J=1.9Hz,4.6Hz,2H) Mass,m/e:305(M+),63(base) b) 5-[(2-Chlorophenyl)acetylaminol-3-(2,6-dichlorophenyl)-4 10 (4-pyridyl)isozazole IH-NMR(DMSO-d 6 )5:11.44(bs,1H),8.44(dd,J=1.7Hz,4.6Hz,2H), 7.67-7.58(m,3H),7.46-7.40(m,2H),7.33-7.29(m,2H), 6.99(dd,J=1.7Hz,4.6Hz,2H),3.93(s,2H) 15 Mass,m/e:457(M+), 125(base) Example 37 3-(2,6-Dichlorophenyl)-5-(3-phenylpropionylamino)-4-(4-pyridyl) isoxazole 20 1H-NMR(CDCl)8:8.38(dd,J=1.5Hz,4.4Hz,2H),8.10(bs,1H), 7.38-7.18(m,8H),6.86(dd,J=1.5Hz,4.4Hz,2H), 3.01(t,J=7.3Hz,2H),2.78(t,J=7.3Hz,2H) Mass,m/e:437(M+),9 1(base) 25 Example 38 3-(3,5-Dichlorophenyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole a) 5-Amino- 3-(3.5- dichlorophenyl) -4- (4-pyridvl)isoxazole 30 IH-NMR(DMSO-d 6 )8:8.47(dd,J=1.6Hz,4.5Hz,2H), 7.75(t,J=1.9Hz,1H),7.41-7.37(bs,2H),7.35(d,J=1.9Hz,2H), 7.06(dd,J=1.6Hz,4.5Hz,2H) Mass, m/e:305(M+), 63(base) 33 b) 3-(3,5 -Dichiorophenyl) 5-(phenylacetylamino) -4- (4-pyridyl) isoxazole IH-NMR(CDCl 3 )5:8.52(dd,J=1 .5Hz,4.4Hz,2H), 7.60(bs, iH), 5 7.42-7.36(m,4H),7.287.23(m,4H),6.89(dd,J=1.5Hz,4.4Hz,2H), 3.76 (s, 2H) Mass, m/e: 423(M+), 9 1 (base) Example 39 io 5- [(2- Fluorophenyi) acetylamino] 3-(3,5. dichlorophenyl) 4- (4-pyridyi) isoxazole 1H-NMR(CDCl 3 )5:8 .53(dd,J=4. 5Hz,6. 2Hz,2H), 7.79-7.72(bs, 1H),7.42(t,J=1.7Hz, 1H),7.39-7.09(m,6H), 15 6.97(dd,J=4.5Hz,6.2Hz,2H),3.77(s,2H) Mass, m/e: 44 1(MI), 109 (base) Example 40 5- [(2- Chlorophenyl)acetylamino] -3-(3. Sdichlorophenyl) -4- (4-p~yridyl) 20 isoxazole IH-NMR(CDCl 3 )8:8.55(dd,J=4.4Hz,6. 2Hz,2H), 7.55-7.50(bs, 1H),7.47-7.40(m,2H), 7.36-7.29(m,3H), 7.28-7.24(m,2H),6.99(dd,J=4.4Hz,6.2Hz,2H),3.87(s,2H) 25 Mass,m/e&457(M'), 125(base) Example 41 3 -(3.5 -Dichlorop~henyl) 5- (3-phenylpropionylamino)-4-(4-pyridyl) isoxazole 30 LH-NMR(CDCl3)5:8. 54(dd,J=1 .6Hz,4.3Hz,2H), 7.56-7.52(bs, 1H),7.42(t,J=1.9Hz, 1H),7.33-7. 16(m,7H), 6.96(dd,J=1.6Hz,4.3Hz,2H),3.01(t,J=7.3Hz,2H), 2.7 5(t,J=7. 3Hz,2H) 35 Mass, m/e:43 7(MI), 9 1(base) 34 Example 42 5-(Phenylacetylamino)-4-(4-pyridyl)-3-(2,3,4-trifluorophenvl)isoxazole a) 5-Amino-4-(4-pyridyl)-3-(2,3,4-trifluorophenl)isoxazole 5 1H-NMR(CDC1 3 )S:8.53(dd,J=1.5Hz,4.4Hz,2H),7.23-7.19(m, IH), 7.09-7.03(m, 1H),6.99(dd,J=1.5H,4.4Hz,2H),4.95(bs,2H) Mass, m/e: 291 (M+),63(base) 10 b) 5-(Phenylacetylamino)-4-(4-pyridyl)-3-(2,3,4-trifluorophenyl) isoxazole 1H-NMR(CDCl 3 )S:8.45(dd,J=1.5Hz,4.6Hz,2H),7.67(bs, 1H), 7.43-7.35(m,3H),7.30-7.27(m,2H),7.22-7.18(m, 1H), 15 7.09-7.05(m, 1H),6.80(dd,J=1.5Hz,4.6Hz,2H),3.77(s,2H) Mass, m/e:409(M+),9 1 (base) Example 43 5-[2-(2-Chlorophenyl)acetylaminol-4-(4-pyridyl)-3-(2,3,4 20 trifluorophenyl)isoxazole 1H-NMR(CDC1 3 )6:8.47(dd,J=1.5Hz,4.2Hz,2H),7.75(bs,1H), 7.35-7.30(m,4H),7.23-7.19(m,1H),7.10-7.03(m,1H), 6.90(dd,J=1.5Hz,4.2Hz,2H),3.89(s,2H) 25 Mass,m/e:443(M+), 125(base) Example 44 5-(Phenylacetylamino)-4-(4-pyridyl)-3-(2,4,5-trifluorophenvl) isoxazole 30 a) 5-Amino-4- (4-pyridyl)- 3 -(2,4,5-trifluorophenyl)isoxazole. 1H-NMR(CDCl 3 )8:8.53(dd,J=1.5Hz,4.6Hz,2H), 7.40-7.34(m,1H),7.00-6.92(m,3H),4.94(bs,2H) Mass,m/e:29 1 (M+),63(base) 35 35 b) 5-(Phenylacetylamino)-4-(4-pyridyl)-3-(2,4,5-trifluorophenyl) isoxazole 1H-NMR(CDCl 3 )8:8.45(dd,J=1.5Hz,4.2Hz,2H),7.63(bs,1H), 5 7.41-7.28(m,7H),6.94-6.88(m,1H),6.80(dd,J=1.5Hz,4.2Hz,1H), 3.77(s,2H) Mass, m/e:409(M+),9 1 (base) Example 45 io 5-[2-(2-Chlorophenyl)acetylaminol-4-(4-pyridyl)-3-(2,4,5 trifluorophenyl)isoxazole 1H-NMR(CDCls)8:8.47(dd,J=1.5Hz,4.6Hz,2H),7.69(bs, 1H), 7.47-7.44(m, 1H),7.37-7.30(m,4H),6.95-6.89(m,3H)3.89(s,2H) 15 Mass,m/e:443(M+), 125(base) Example 46 5-(3-Phenylpropionylamino)-4-(4-pyridyl)-3-(2,4,5-trifluorophenyl) isoxazol 20 1H-NMR(DMSO-d 6 )8:11.00(bs,1H),8.47(dd,J=1.5Hz,4.4Hz,2H), 7.83-7.66(m,2H),7.32-7.28(m,2H),7.23-7.20(m,3H), 7.01(dd,J=1.5Hz,4.4Hz,2H),2.88(t,J=7.3Hz,2H), 2.71(t,J=7.3H,2H) 25 Mass,m/e:423(M+),9 1(base) Example 47 5-(Phenylacetylamino)-4-(4-pyridyl)-3-(2,4,6-trifluorophenyl)isoxazole a) 5-Amino-4- (4-pyridyl)- 3 -(2.4,6 -trifluorophenyl)isoxazole 30 1H-NMR(CDCl 3 )8:8.51(dd,J=1.5Hz,4.6Hz,2H), 7.03-6.64(m,4H),4.96(bs,2H) Mass,m/e:29 1(M+),63(base) 36 b) 5-(Phenylacetylamino)-4-(4-pyridyl)-3-(2,4,6-trifluorophenyl) isoxazole H-NMR(CDCl 3 )8:8.45(dd,J=1.5Hz,4.6Hz,2H),7.53(bs,1H), 5 7.43-7.35(m,3H),7.29-7.27(m,2H),6.81(dd,J=1.5Hz,4.4Hz,2H), 6.75-6.70(m,2H),3.78(s,2H) Mass,m/e:409(M+),9 1 (base) Example 48 10 5-[2-(2-Chlorophenyl)acetylaminol-4-(4-pyridyl)-3-(2,4,6 trifluorophenyl)isoxazole 1H-NMR(CDC1 3 )8:8.46(dd,J=1.5Hz,4.4Hz,2H),7.77(bs,1H), 7.47-7.45(m,1H),7.37-7.30(m,3H),6.91(dd,J=1.5Hz,4.4Hz,2H), 15 6.76-6.70(m,2H),3.90(s,2H) Mass,m/e:443(M+), 125(base) Example 49 5-(3-Phenylpropionylamino)-4-(4-pyridyl)-3-(2,4,6-trifluorophenyl) 20 isoxazole 1H-NMR(DMSO-d 6 )S:11.10(bs,1H),8.46(dd,J=1.5Hz,4.2Hz,2H), 7.44-7.39(m,2H),7.32-7.29(m,2H),7.23-7.20(m,3H), 6.98(dd,J=1.5Hz,4.2Hz,2H),2.89(t,J=7.3Hz,2H), 25 2.73(t,J=7.3H,2H) Mass,m/e:423(M+),9 1 (base) Example 50 5-(Phenylacetylamino)-4-(4-pyridyl)-3-(3,4,5-trifluorophenyl)isoxazole 30 ) 5-Amino-4- (4-pyridyl)- 3 -(3,4,5-trifluorophenyl)isoxazole 1H-NMR(CDC 3 ):8.58(dd,J=1.9Hz,4.6Hz,2H), 7.09-7.05(m,4H),4.90(bs,2H) Mass,m/e:29 1(M+,base) 35 37 b) 5 -(Phenylacetylamino) -4- (4-pyridyl) -3- (3,4,5-trifluorophenyl) isoxazole 1H-NMR(CDCl 3 )8:8.52(dd,J=1.5Hz,4.4Hz,2H),7.66(bs,iH), 5 7.41-7.23(m,5H),7.01(dd,J=6.5Hz,8.OHz,2H), 6.90(dd,J=1.5Hz,4.4Hz,2H),3.74(s,2H) Mass, m/e:409(M+),9 1(base) Example 51 10 5-[(2-Chlorophenyl)acetylamino]-4-(4-pyridyl)-3-(3,4,5 trifluorophenyl)isoxazole IH-NMR(CDCl 3 )S:8.54(dd,J=1.5Hz,4.4Hz,2H),7.76(bs, 1H), 7.44-7.42(m, 1H),7.33-7.28(m,3H),7.02(dd,J=6.5Hz,7.7Hz,2H), 15 6.99(dd,J=1.5Hz,4.4Hz,2H),3.85(s,2H) Mass,m/e:443(M+), 125(base) Example 52 5-(3-Phenvlpropionylamino)-4-(4-pyridyl)-3-(3,4,5-trifluorophenyl) 20 isoxazole 1H-NMR(DMSO-d 6 )8:10.93(bs,1H),8.52(dd,J=1.7Hz,4.4Hz,2H), 7.36(dd,J=6.9Hz,8.4Hz,2H),7.30-7.27(m,2H),7.23-7.19(m,3H), 7.09(dd,J=1.7Hz,4.4Hz,2H),2.86(t,J=7.5Hz,2H), 25 2.68(t,J=7.5Hz,2H) Mass,m/e:423(M+),9 1(base) Example 53 3-(2-Methoxyphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) 30 isoxazole a) 5-Amino- 3- (2-methoxyphenyl) -4- (4-pyridvl)isoxazole 1H-NMR(CDCl3)6:8.45(dd,J=4.6Hz,6.2Hz,2H),7.49-7.40(m,2H), 7.04(td,J=1.0Hz,7.8Hz,1H),6.97(dd,J=4.6Hz,6.2Hz,2H), 35 6.85(d,J=7.8Hz,1H),4.88-4.77(bs,2H),3.37(s,3H) 38 Mass, m/e:267(M+), 63(base) b) 3-(2-Methoxyp~henyl) 5-(phenylacetylamino) -4- (4-pyridyl) isoxazole 5 LH-NMR(CDC1 3 ):8.39(dd,J=1 .5Hz,4.2Hz,2H), 7.53-7.26(m, 7H),7.04(td,J=0.8Hz, 7.7Hz, 1H),6.82-6.75(m,3H), 3.78(sH),.24(sH) Mass, m/e: 385(M+), 9 1(base) 10 Example 54 5- [(2- Chlorophenyl)acetvlamino] -3-(2- methoxyphenyl) -4- (4-pyridyl) isoxazole 15 1H-NMR(CDCla):8.40(d,J=6.OHz,2H),7.58-7.51(bs, 1H), 7.5O-7.28(m,6H),7.O5(t,J=7.3Hz, 1H),6.88(d,J=6.OHz,2H), 6.80(d,J=8.5Hz, 1H),3.90(s,2H),3.25(s, 3H) Mass, m/e:419 (M+), 125(base) 20 Example 55 3- (2-Methoxyphenyl)S. (3-phenylipropionylamino) -4- (4-p3yridvi) isoxazole IH-NMR(CDCl 3 ):8.42(d,J=5.8Hz,2H),7.6 1-7.54(bs, iH), 25 7.50-7.40(m,2H),7.32-7. 17(m,5H),7.05(m, iH), 6.87(dd,J=1.5Hz,4.6Hz,2H),6.80(d,J=8. 1Hz, iH), 3.26(s,3H),3.O1(t,J=7.3Hz,2H),2.76(t,J=7.3Hz,2H) Mass, m/e: 399(MI), 9 1 (base) 30 Example 56 . 3- (4-Methoxyphenvi) -5- (phenylacetylamino) -4- (4- pyridyl)isoxazole a) 5 -Amino- 3 -(4-methoxvphenyl)-4- (4-pyridyl)isoxazole IH-NMR(CDCl 3 )8:8.54(dd,J=1.5Hz,4.6Hz,2H), 35 7.35(dt,J=2.5Hz,8.9Hz,2H),7.07(dd,J=1.5Hz,4.6Hz,2H), 39 6.88(dd,J=2.5Hz,8.9Hz, 2H), 4. 76(bs, 2H), 3.82(s, 3H) Mass, m/e:267(M+), 63(base) b) 3-(4-Methoxyphenyl) 5-(phenylacetylamino) -4- (4-pyridyl) 5 isoxazole 1H-NMR(DMSO-d 6 )8: 1O.99(bs, 1H),8.46(dd,J=1.5Hz, 4.2Hz, 2H), 7.36-7.24(m, 7H), 7.06(dd,J=1.5Hz,4.2Hz,2H), 7.02-6.97(m,2H), 3.7 8(s, 3H),3.67 (s, 2H) 10 Mass, m/e: 385(M+), 9 1(base) Example 57 5- [(2-Chlorophenyl)acetylaminol -3- (4- methoxyvheny1) 4-(4-pvridyl) isoxazole 15 1H-NMR(CDC1 3 )8:8.50(dd,J=1.5Hz,4.4Hz,2H),7.53(bs, 1H), 7.45-7.42(m, 1H),7.35-7.26(m,5H),7.O(dd,J=1.5Hz,4.4Hz,2H), 6.88-6.84(m,2H),3.87(s,2H), 3.81 (s, 3H) Mass, m/e:419 (M+), 125(base) 20 Example 58 3-(4-Methoxvphenyl> 5- (3-phenvipropionylamino) -4-(4-pyridyl) isoxazole 25 1H-NMR(CDCl 3 )5:8.48(dd,J=1.4Hz,4.5Hz,2H),7.77(bs, 1H), 7.32-7. 16(m, 7H),6.98(dd,J=1.4Hz,4.5Hz,2H),6.88&6.83(m,2H), 3.81(s,3H),3.O(t,J7.4Hz,2H),2.75(t,J=7.4Hz,2H) Mass, m/e: 399(M+), 9 1 (base) 30 Example 59 5- [(2-Chlorophenyl)propionylaminol - 3-(4-methoxyphenyl) -4 (4-pyridyDisoxazole 1H-NMR(DMSO-d 6 )5: 1.81(bs, 1H),8.5 1(dd,J=1.5Hz,4.6Hz,2H), 35 7.44-7.41(m, 1H),7.30-724(m,5H),7.09(dd,J=1.5Hz,4.6Hz,2H), 40 6.99(d,J=6.6Hz,2H),3.79(s,3H),2.95(t,J=7.3Hz,2H), 2.69 (t,J=7.3Hz, 2H) Mass, m/e:43 3(MI), 26 7(base) 5 Example 60 5-[(3-Chlorophenyl)propionylamino] -3- (4-methoxyphenyl) -4 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 ):8.46(d,J=5.8Hz,2H), 7.99(bs, iH), 10 7.28(d,J=8.9Hz,2H),7.20-7. 18(m,3H),7.07-7.05(m, 1H), 6.99(d,J=5.8Hz,2H),6.85(d,J=8.9Hz,2H), 3.81(s,3H), 2.97(t,J=7. lHz,2H),2.74(t,J=7. lHz,2H) Mass, m/e:43 3(M+), 135(base) 15 Example 61 5- [(4- Chlorophenyl)propionylaminol -3- (4- methoxyphenyl) -4 (4-pyridyl)isoxazole IH-NMR(DMSO-d6)5: 10.77(bs, 1H),8.50(dd,J=1 .7Hz,4.4Hz,2H), 20 7.33(d,J=8.3Hz,2H),7.28(d,J=8.9Hz,2H),7.22(d,J=8.3Hz,2H), 7.06(dd,J=1.7Hz,4.4Hz,2H),6.99(d,J=8.9Hz,2H),3.78(s,3H), 2.84(t,J=7.3Hz,2H), 2.66(t,J=7.3Hz, 2H) Mass,m/e:433(M+), 125(base) 25 Example 62 3 -(4-Methoxyphenyl) 5- [(2-Methylphenyl)propion-vlamino] -4 (4-pyridyl)isoxazole 1H-NMR(DMSO-d 6 )5: 1O.77(bs, 1H),8.5 i(dd,Ji .5Hz, 4.6Hz, 2H), 30 7.29(d,J=8.9Hz,2H),7.16-7.1O(m,4H), 7.08(dd,J=1.5Hz, 4.6Hz, 2H),6.99(d,J=8.9Hz, 2H), 3.78(s,3H),2.83(t,J=7.5Hz,2H),2.62(t,J=7.5Hz, 2H),2.27(s,3H) Mass, m/e:413(M+), 105(base) 35 Example 63 41 3-(4-Methoxyphenvyl)-5- [(3-methylphenyl)propionylamino] -4 (4-pyridyl)isoxazole 1H-NJMR(CDC1 3 )8:8.47(d,J5.8Hz,2H), 7. 73(bs, 1H), 5 7.28(d,J=8.6Hz,2H), 7. 17(t,J=7.7Hz, 1H),7.04-7.OO(m,3H), 6.97(d,J=5.8Hz, 2H), 6.85(d,J=8.6Hz, 2H), 3.80(s, 3H), 2.96(t,4=7.3Hz,2H), 2.73(t,J=7.3Hz, 2H), 2.3 1(s, 3H) Mass, m/e:413(M+), 105(base) 10 Example 64 3 -(4- Ethoxyphenyl) -S.(phenylacetylamino)-4-(4-pyridyl)isoxazole a) 5 -Amino- 3 -(4-ethoxyphenyl)- 4- (4-pyridvl)isoxazole 1H-NMR(CDCL 3 )5:8.52(dd,J=1 .6Hz,4. 5Hz, 2H), 15 7.33(dt,J=2.5Hz,8.9Hz,2H),7.07(dd,J=1.6Hz,4.5Hz,2H), 6.87(dt,J=2.5Hz,8.9Hz,2H),4.83(bs,2H),4.04(q,J=6.9Hz, 2H), 1 .42(t,J=6.9Hz, 3H) Mass, m/e:28 1(M+,base) 20 b) 3- (4- Ethoxvphenyl) 5-(phenylacetylamino) -4- (4-pyridyl) isoxazole 1H-NMR(CDC1 3 )5:8.46(dd,J=1 .9Hz,4.6Hz,2H),7.55(bs, 1H), 7.40-7.31(m,3H),7.277.24(m,4H),6.91(dd,J=1.9Hz,4.6Hz,2H), 25 6.83(d,J=8.9Hz,2H),4.02(q,J=6.9Hz,2H),3.75(s,2H), 1 .40(t,J=6.9Hz, 3H) Mass, m/e:399(M+), 9 1 (base) Example 65 30 5-(2-Chlorophenylacetylamino-3-(4-ethoxyphenl)Y4-(4-pyridyl) isoxazole 1H-NMR(DMSO-d6)5: 11 .02(bs, 1H),8.52(dd,Jl .9Hz,4.6Hz,2H), 7.44-7.42(m, 1H),7.38-7.36(m, iH), 7.32-7.27(m,4H), 35 7. 16(dd,J=1.9Hz,4.6Hz,2H),6.97(d,J=8.9Hz,2H), 42 4.05(q,J=6.9Hz,2H), 3.75(s,2H), 1 .32(t,J=6.9Hz,3H) Mass, m/e: 433(M+), 1 25(base) Example 66 5 3-(4-Ethoxyphenyl)5-(3-phenylp~ropionylamino)-4-(4-pyridvl) isoxazole 1H.NMR(CDCl 3 )5:8.46(dd,J=1. .5Hz, 4.4Hz, 2H), 7. 76(bs, 1iH), 7.30- 7. 17(m, 7H), 6.97(dd,J=1. 5Hz, 4.4Hz, 2H), 10 6.83(d,J=8.9Hz,2H),4.02(q,J=6.9Hz,2H),2.99(t,J=7.5Hz,2H), 2.74(t,J= 7.5Hz, 2H), 1.40(t,J=6.9Hz,3H) Mass, m/e:41 3(M+), 9 1 (base) Example 67 15 3- (2- Fluoro-4-methoxyphenyl) -5-(phenylacetylamino) -4-(4-pyridyl) isoxazole a) 5 -Amino- 3 -(2 -fluoro- 4methoxyphenyl) -4- (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )5:8.49(dd,J=1 .5Hz,4.6Hz,2H),7.38(t,J=8.2Hz, iH), 20 7.00(dd, 1.5Hz,4.6Hz,2H),6.76(dd,J=6. lHz,8.2Hz, iH), 6.6 1(dd,J=2.7Hz, 11.9Hz, 1H),4.84(bs,2H),3.82(s,3H) Mass, m/e:28 5(M+), 6 3(base) b) 3-(2- Fluoro-4-methoxyphenyl) -5- (phenylacetylamino)-4 25 (4-pvridvl~isoxazole Example 68 5- [(2- Chlorophenyl)acetylaminol -8 (2-fluoro-4methoxvp~henyl) (4-pyridyl~isoxazole 30 IH-NMR(DMSO-d6)5: 11. 19(bs, 1H),8.48(dd,J=1.5Hz, 4.6Hz, 2H), 7.48-7.38(m, 3H), 7.33-7.28(m,2H), 7.09(dd,J=1.5Hz,4.6Hz,2H), 6.94(s, 1H),6.91-6.90(m, 1H),3.90(s,2H),3.8 1(s,3H) Mass, m/e:437(M+), 125(base) 35 43 Example 69 3-(2- Fluoro-4-methoxyphenyl)-5-(3-phenylpropionvlamino)-4 (4-pyridyl)isoxazole 5 IH-NMR(CDC1 3 )8:8.37(d,J5.78Hz,2H),7.34(t,J=8.oHz, iH), 7.30-7. 17(m, 5H),6.88(dd,J=1.5Hz,4.2Hz, 2H), 6.74(dd,J=2.3Hz,8.48Hz, 1H),6.56(dd,J=2.3Hz, 11.5Hz, iH), 3.79(s,3H),3.0(t,J7.3Hz,2H),2.76(t,J=7.3Hz,2H) Mass, m/e:41 7(MI), 9 1 (base) 10 Example 70 3- (4- Fluoro-3 -methoxyphenyl) -5- (phenylacetylamino) -4- (4-pyridyvl) isoxazole a) 5 -Amino-3 -(4-fluoro-3 -methoxyphenyl) - -(4 -pyridyl)isoxazole 15 IH-NMR(CDCl 3 )8:8.55(dd,J=1 .7Hz,4.4Hz,2H),7. 10-7.0 1(m,4H), 6.91 -6.87(m, 1H),4.87(s,2H),3.78(s,3H) Mass, m/e:285(M+), 151(base) 20 b) 3 -(4-Fluoro- 3-methoxyphenyl) 5 (phenylacetylamino) -4 (4-pyridvl)isoxazole IH-NR(CC13):8.0(ddJ=17Hz,4.4Hz,2H),7.53(bs, 1H), 7.42-7.35(m,4H),7.28-7.24(m, 1H),7.05-6.98(m,2H), 25 6.92(dd,J1.7Hz,4.4Hz,2H),6.83-6.79(m, 1H),3.76(bs,2H), 3.75(s, 3H) Mass, m/e:403(M+),9 1 (base) Examole 71 30 -5- [(2- Chlorophenvl)acetylaminol -3- (2-fluoro-4-methoxvphenyl) -4 (4-pyridyl~isoxazole IH-NMR(CDC1 3 )5:8.5 i(dd,J=i .5Hz,4.2Hz,2H),7.63(bs, 1H), 7.46-7.42(m, 1H),7.35-7.28(m,3H),7.05-6.99(m,4H), 35 6.85-6.80(m, 1H),3.87(s,2H),3.75(s,3H) 44 Mass,m/e:437(M+), 125(base) Example 72 3-(4-Fluoro-3-methoxyphenyl)-5-(phenylpropionylamino)-4 5 (4-pyridyl)isoxazole 1H-NMR(CDCla)8:8.51(dd,J=1.5Hz,4.6Hz,2H),7.69(bs,1H), 7.32-7.16(m,5H),7.05-7.01(m,2H),6.98(dd,J=1.5Hz,4.6Hz,2H), 6.84-6.79(m,lH),3.74(s,3H),3.00(t,J=7.3Hz,2H), 10 2.75(t,J=7.3Hz,2H) Mass,m/e:417(M+),9 1 (base) Example 73 3-(2,3-Dimethoxyphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) 15 isoxazole a) 5-Amino- 3 -(2,3 - dimethoxyphenyl)-4- (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )S:8.43(dd,J=1.7Hz,4.5Hz,2H), 7.09(t,J=7.7Hz,1H),7.02(dd,J=1.7Hz,8.5Hz,1H), 20 6.99(dd,J=1.7Hz,4.5Hz,2H),6.92(dd,J=1.7Hz,7.7Hz,1H), 4.91-4.85(bs,2H),3.86(s,3H),3.59(s,3H) Mass,m/e:297(M+),5 1(base) b) 3-(2,3-Dimethoxyphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) 25 isoxazole IH-NMR(CDCl 3 )6:8.36(dd,J=1.5Hz,4.6Hz,2H), 7.65-7.58(bs,1H),7.43-7.33(m,3H),7.29(d,J=6.2Hz,2H), 7.09(t,J=7.8Hz,1H),7.01(dd,J=1.5Hz,8.5Hz,1H), 30 6.90(dd,J=1.5Hz,7.8Hz,1H),6.80(dd,J=1.5Hz,4.6Hz,2H), 3.83(s,3H),3.79(s,2H),3.48(s,3H) Mass,m/e:415(M+),9 1(base) Example 74 45 5- [(2- Chlorophenvl)acetvlaminol -3 -(2.3- dimethoxyphenyl) -4 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 ):8.38(d,J=5.8Hz,2H), 7.83-7.75(bs, IH), 5 7.50- 7.27(m,4H), 7.09(t,J=8.OHz, IH), 7.01(dd,J=1.5Hz,8.OHz, 1H),6.94-6.89(m,3H),3.90(s,2H), 3.83(OH),.49(OH) Mass, mI&:449(MI) , 1 25(base) 10 Example 75 3-(2. 3Dimethoxyphenl5(3-phelpropioflylamilo)-4 (4-pyridvl~isoxazole 1H.NMR(CDCl 3 )5:8.37(dd,J=1 .5Hz,4.6Hz,2H), 15 8.0O-7.80(bs, 1H),7.32-7. 17(m,5H),7. 10(t,J=8.5Hz, iH), 7.02(dd,J=1.5Hz,8.5Hz, 1H),6.91(dd,J=1.5Hz,7.7Hz, 1H), 6.89(dd,J=1.5Hz,4.6Hz,2H),3.83(s, 3H), 3.50(s,3H), 3.01 (t, J=7.3Hz, 2H), 2. 76(t, J=7.3Hz, 2H) Mass, m/e:429(MI),9 1 (base) 20 Example 76 3- (3.4-Dimethoxyphenyi) -5-(phenylacetylamino) -4- (4-pyridyl) isoxazole a) 5 -Amino- 3- (3. 4-dimethoxyphenyl) -4- (4-p-vridvl)isoxazole 25 IH-NMR(CDCl 3 ):8.55(dd,J=1.5Hz,4.2Hz,2H), 7. 1(dd,J=1.5Hz,4.2Hz,2H),6.99(d,J4 .9Hz, 1H), 6.93(dd,J=1.9Hz,8.3Hz, 1H),6.82(d,J=8.3Hz, iH), 4.80(s,2H),3.89(s,3H),3.76(s, 3H) 30 Mas-S,m/e:297(M+), 164(base) b) 3- (3, 4Dimethoxyphenyl) 5-(phenylacetylamino) -4-(4-pyridyl) isoxazole 35 1H-NMR(CDC 3 ):8.50(d,J=4.4Hz,6.2Hz,2H),7.42-7.33(m,4H), 46 7.28-7.23(m, 2H),6.96-6.93(m,3H),6.85(dd,J=1.9Hz,8.3Hz, 1H), 6.79(d,J=8.3Hz, 1H),3.87(s,3H),3.76(s,2H),3.73(s, 3H) Mass, m/e:415 (MI), 9 1 (base) 5 Example 77 5- [(2- Fluorophenyl)acetylaminol -3- (3,4-dimethoxyphenyl) -4 (4-pyridyl)isoxazole 1H-NMR(CDC13)5:8. 51(dd,J=4. 4Hz,6.OHz, 2H), 10 7.54-7.48(bs, 1H),7.39-7.08(m,4H),7.02(dd,J=4.4Hz,6.OHz,2H), 6.95(d,J=2. 1Hz, 1H),6.87(dd,J=2. lHz,8.2Hz, 1H), 6.79(d,J=8.2Hz, iH), 3.88(s,3H),3.77(s,2H),3.73(s, 3H) Mass,m/e:433(M+), 109(base) 15 Example 78 5- [(2- Chlorophenyl)acetylamino] -3-(3,4-dimethoxyphenyl) -4 (4-pyridvl)isoxazole IH-NMR(CDCl 3 )5:8. 51 (dd,J=4.6Hz,6.2Hz, 2H), 20 7.56-7.51l(bs,1IH),7.47-7.40(m, 1H), 7.35-7.27(n,3H), 7.03(dd,J=4.6Hz,6.2Hz,2H),6.94(d,J=1.9Hz, 1H), 6.87(dd,J=1.9Hz,8.3Hz, 1H),6.79(d,J=8.3Hz, 1H), 3.87(s,3H),3.87(s,2H),3.73(s,3H) Mass,m/e&449(MI), 1 25(base) 25 Example 79 3- (3. 4Dimethoxyphenyl) 5-(3 -phenylpropionylamino)-4-(4-pyridyl) isoxazole 30 IH-NMR(CDCl 3 )5:8.53(dd,J=1.6Hz,4.3Hz,2H),7.33-7. 14(m.,5H), 7.02(dd,J=1.6Hz,4.3Hz,2H),6.94(d,J=1.9Hz, 1H), *6.86(dd,J=1.9Hz,8.5Hz, LH),6.79(d,J=8.5Hz, 1H), 3.88(s,3H),3.73(s,3H),3.O(t,J7.4Hz,2H),2.75(t,J=7.4Hz,2H) Mass, m/e:429 (M+), 9 1 (base) 35 47 Example 80 3- (2. 6-Dimethoxyphenyl) 5-(phenylacetylamino) -4- (4-pyridyl) isoxazole 5 1H-NMR(CDCl 3 )5:8.35(dd,J=1.5Hz,4.4Hz,2H),7.57(bs, 1H), 7.39-7.28(m,6H),6.79(dd,J=1.5Hz,4.4Hz,2H), 6.54(d,J=8.5Hz,2H), 3.77(s,2H),3.58(s,6H) Mass, m/e:4 15 (MI), 9 1 (base) 10 Example 81 5- [2- (2- Chlorophenyl)acetylamino] -3- (2, 6dimethoxyphenyl) 4- (4-pyridvl)isoxazole 1H-NMR(DMSO-d6)8: 11. 13(bs, I1H), 8.39 (dd- like, 2H), 15 7.47-7.40(m,3H),7.347.30(m,2H),6.98(dd,J=1.5Hz,4.6Hz,2H), 6. 75(d,J=8.5Hz,2H), 3.90(s, 2H), 3.59(s,6H) Mass, m/e:450 (MI), 125(base) Example 82 20 3 -(2. 3-Methylenedioxyphenyl) 5 -(phenylacetylamino) -4- (4-pyridyl) isoxazole a) 5 -Amino- 3 -(2,3 -methylenedioxyphen-vi) -4- (4-pyridyl)isoxazole 1H-NMR(CDCl 3 ):8.52(dd,J=1.5Hz,4.6Hz,2H), 25 7.08(dd,J=1.5Hz,4.6Hz, 1H),6.91-6.80(m,4H), 5.78(s,2H),4.88(bs, 2H) Mass, m/e:28 1(MI), 63(base) b) 3- (2.3 -Methylenedioxy-phen-vi)-5- (phenylacetyvlamino) -4 30 (4-p-vridyl)isoxazole IH-NMR(CDCl 3 )5:8.45(dd,J=1 .5Hz,4.6Hz,2H),7.56(bs, 1H), 7.41-7.36(m,3H),7.28-7.26(m,2H),6.90-6.81(m,5H), 5. 70(s, 2H),3.77(s, 2H) 35 Mass, m/e:399(M'), 9 1(base) 48 Example 83 3-(2,3-Methylenedioxyphenyl)-5-[2-(2-chlorophenyl)acetylaminol-4 (4-pyridyl)isoxazole 5 1H-NMR(CDC1 3 )8:8.47(dd,J=1.5Hz,4.6Hz,2H),7.63(bs, 1H), 7.45-7.43(m, 1H),7.35-7.29(m,3H),6.99(dd,J=1.5Hz,4.6Hz,2H), 6.89-6.81(m,3H),5.71(s,2H),3.88(s,2H) Mass,m/e:433(M+), 125(base) 10 Example 84 3-(3,4-Methylenedioxyphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole a) 5-Amino- 3-(3,4-methylenedioxyphenyl) -4- (4-pyridyl)isoxazole 15 1H-NMR(DMSO-d)6:8.41(dd,J=1.5Hz,4.6Hz,2H),7.18(bs,2H), 7.04(dd,J=1.5Hz,4.6Hz,2H),6.93(d,J=8.1Hz,1H), 6.82(d,J=1.5Hz,1H),6.78(dd,J=1.5Hz,8.1Hz,1H),6.05(s,2H) Mass,m/e:281(M+), 148(base) 20 b) 3-(3,4-Methylenedioxyphenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )6:8.49(dd,J=1.5Hz,4.2Hz,2H),7.62(bs,1H), 25 7.42-7.35(m,3H),7.28-7.24(m,2H),6.92(dd,J=1.5Hz,4.2Hz,2H), 6.85(d,J=1.5Hz,1H),6.82(dd,J=1.5Hz,8.1Hz,1H), 6.76(d,J=8.1Hz,1H),5.99(s,2H),3.76(s,2H) Mass,m/e:399(M+),9 1(base) 30 Example 85 5-[(2-Chlorophenvl)acetylaminol-3-(3,4-methylenedioxyphenyl)-4 (4-pyridyl)isoxazole IH-NMR(CDCl 3 )8:11.02(bs,1H),8.52(dd,J=1.4Hz,4.7Hz,2H), 35 7.43-7.38(m,1H),7.37-7.33(m,1H),7.32-7.25(m,2H), 49 7.16(dd,J=1.4Hz,4.7Hz,2H),6.95(d,J=8. 1Hz, 1H), 6.89(d,J=1.5Hz, 1H),6.81(dd,J=1.5Hz,8. 1Hz, 1H),6.06(s,2H), 3.84(s,2H) Mass,m/e:433(M+), 125(base) 5 Example 86 3-(3,4-Methylenedioxyphenyl)-5-(3-phenvlpropionylamino)-4 (4-pyridyl)isoxazole 10 1H-NMR(DMSO-d6)5:10.78(s,1H),8.51(dd,J=1.5Hz,4.6Hz,2H), 7.32-7.17(m,5H),7.08(dd,J=1.5Hz,4.6Hz,2H), 6.97(d,J=8.1Hz,1H),6.90(d,J=1.5Hz, 1H), 6.81(dd,J=1.5Hz,8.1Hz,1H),2.86(t,J=7.3Hz,2H), 2.67(t,J=7.3Hz,2H) 15 Mass,m/e:413(M+),91(base) Example 87 3-(3,4-Ethylenedioxyphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 20 a) 5-Amino- 3 -(3,4-ethylenedioxyphenyl) -4-(4-pyridyl)isozazle IH-NMR(DMSO-d 6 )S:8.44(dd,J=1.6Hz,4.5Hz,2H),7.18(bs,2H), 7.06(dd,J=1.6Hz,4.5Hz,2H),6.88(d,J=8.3Hz,1H), 6.81(d,J=2.1Hz,1H),6.76(dd,J=2.lHz,8.3Hz,1H), 25 4.30-4.22(m,4H) Mass,m/e: 295(M+),5 1 (base) b) 3-(3,4-Ethylenedioxyphenyl)-5-(phenylacetylamino)-4 (4-pyridvl)isoxazole 30 1H-NMR(CDCl 3 )S:8.22(dd,J=1.5Hz,4.6Hz,2H),7.51(bs,1H), 7.40-7.32(m,3H),7.25-7.23(m,2H),6.91-6.90(m,3H), 6.79(s,2H),4.28-4.21(m,4H),3.74(s,2H) Mass,m/e:413(M+),9 1(base) 35 50 Example 88 5-[(2-Chlorophenvl)acetylamino]-3-(3,4-ethylenedioxyphenyl) -4 (4-pyridyl) isoxazole 5 1H-NMR(DMSO-d)8:11.02(bs,1H),8.54(dd,J=1.7Hz,4.4Hz,2H), 7.44-7.41(m,1H),7.37-7.27(m,3H),7.18(dd,J=1.7Hz,4.4Hz,2H), 6.90(d,J=8.1Hz,1H),6.85(d,J=1.9Hz,1H), 6.80(dd,J=1.9Hz,8.1Hz,1H),4.28-4.23(m,4H),3.85(s,2H) Mass,m/e:447(M+), 125(base) 10 Example 89 3-(3,4-Ethylenedioxyphenyl)-5-(3-phenylpropionylamino)-4- (pyridyl) isoxazole 15 1H-NMR(DMSO-d 6 )5:10.76(bs,1H),8.51(dd,J=1.5Hz,4.6Hz,2H), 7.30-7.26(m,2H),7.22-7.18(m,3H),7.08(dd,J=1.7Hz,4.6Hz,2H), 6.89(d,J=8. 1Hz, 1H),6.84(d,J=1.9Hz, 1H), 6.78(dd,J=1.9Hz,8. 1Hz, 1H),4.28-4.23(m,4H), 2.85(t,J=7.5Hz,2H), 2.65(t,J=7.5Hz,2H), 20 Mass,m/e:427(M+),91(base) Example 90 5-(Phenylacetylamino)-4-(4-pyridyl)-3-(3-trifluoromethoxyphenyl) isoxazole 25 a) 5-Amino-4- (4-pyridyl)- 3 -(3-trifluoromethoxyphenyl)isozazole 1H-NMR(CDC1 3 )5:8.56(dd,J=1.5Hz,4.4Hz,2H),7.53-7.28(m,4H), 7.05(dd,J=1.5Hz,4.4Hz,2H),4.89(bs,2H) Mass,m/e:32 1(M+),63(base) 30 b) 5-(Phenylacetylamino)-4-(4-pyridyl)-3-(3-trifluoromethoxy phenyl)isoxazole 1H-NMR(CDCl 3 )8:8.50(dd,J=1.5Hz,4.6Hz,2H),7.52(bs,1H), 35 7.40-7.23(m,9H),6.89(dd,J=1.5Hz,4.6Hz,2H),3.76(s,2H) 51 Mass, m/e: 39(M'),9 1 (base) Example 91 5- [2-(2-Chlorophenyl)acetylamino] -4-(4pvvridvl-3-(3-trifluoro 5 methoxyphenyl)isoxazole 1H-NMR(CDCla)5:8.5 i(dd,J=1.5Hz,4.2Hz,2H),7.65(bs, 1H), 7.45-7.37(m,2H),7.357.24(m,6H),6.98(dd,J=1.5Hz,4.2Hz,2H), 3.87(s,2H) 10 Mass, m/e:473(M+), 125(base) Example 92 5- (3-Phenylpropionviamino) -4- (4-pyridyl) -3- (3 -trifluoromethoxy phenvl)isoxazole 15 IH-NMR(CDC1 3 )5:8.53(dd,J=1 .5Hz,4.6Hz,2H), 7.53(bs, lH), 7.43-7.39(m,2H),7.32-7. 17(m, 7H),6.97(dd,J=1.5Hz,4.6Hz,2H), 3.0 1(t,J=7.3Hz,2H),2.75(t,J=7.3Hz,2H) Mass, m/e&453(M'),9 1 (base) 20 Example 93 5- (Phenylacetylamino) -4- (4-pyridyl) 3- (4-trifluoromethoxy phenyl)isoxazole a) 5 -Amino-4- (4-pyridyl) -3 -(4-trifluoromethoxyphenyl) isoxazole 25 1H-J41\R(CDCl 3 ):8.57(dd,J=1 .5Hz,4.5Hz,2H), 7.53-7.40(m,2H), 7. 19-7.02(m,4H),4.85(bs,2H) Mass, m/e:32 1 (M+,base) 30 b) 5-(Phenylacetylamino) -4(4-pvridyl) -3-(4-trifluoro methoxyphenyl)isoxazole 1H-NM~R(CDC1 3 )8:8.50(dd,J=1 .5Hz,4.2Hz,2H), 7.59(bs, 1H), 7.42-7. 18(m,9H),6.90(dd,J=1.5Hz,4.2Hz,2H),3.75(,2H) 35 Mass, m/e:439(MI), 9 1(base) 52 Example 94 5-[2-(2-Chlorophenyl)acetylaminol-4-(4-pyridyl)-3-(4-trifluoro methoxyphenvl)isoxazole 5 1H-NMR(CDCl 3 )5:8.52(dd,J=1.5Hz,4.2Hz,2H),7.56(bs,1H), 7.46-7.40(m,3H),7.34-7.29(m,3H),7.21-7.19(m,2H), 6.99(dd,J=1.5Hz,4.2Hz,2H),3.87(s,2H) Mass,m/e:473(M+), 125(base) 10 Example 95 3-(2-Methylphenvl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole a) 5-Amino- 3 -(2-methylphenyl) -4-(4-pyridyl)isoxazole 15 1H-NMR(CDCl 3 ):8.42(dd,J=1.6Hz,4.5Hz,2H),7.38-7.32(m,1H), 7.30-7.21(m,3H),6.89(dd,J=1.6Hz,4.5Hz,2H),4.95(s,2H), 2.10(s,3H) Mass,m/e:25 1 (M+),65(base) 20 b) 3-(2-Methylphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 1H-NMR(CDCl 3 )S:8.36(dd,J=4.6Hz,6.2Hz,2H), 7.66-7.61(bs, 1H),7.45-7.28(m,6H),7.24-7.17(m,3H), 25 6.71(dd,J=4.6Hz,6.2Hz,2H),3.81(s,2H),2.03(s,3H) Mass, m/e:369(M+),9 1 (base) Example 96 5-[(2-Fluorophenyl)acetylamino]-3-(2-methylphenyl)-4-(4-pyridyl) 30 isoxazole 1H-NMR(CDCl 3 )6:8.37(dd,J=4.5Hz,6.2Hz,2H), 7.90-7.80(bs, 1H),7.39-7.29(m,4H),7.25-7.10(m,4H), 6.80(dd,J=4.5Hz,6.2Hz,2H),3.82(s,2H),2.04(s,3H) 35 Mass,m/e:387(M+), 109(base) 53 Example 97 5-[(2-Chlorophenyl)acetylaminol-3-(2-methylphenyl)-4-(4-pyridyl) isoxazole 5 1H-NMR(CDCl 3 )8:8.38(dd,J=4.6Hz,6.OHz,2H), 7.67-7.62(bs,1H),7.49-7.44(m,1H),7.40-7.30(m,4H), 7.24-7.18(m,3H),6.82(dd,J=4.6Hz,6.OHz,2H),3.92(s,2H), 2.04(s,3H) 10 Mass,m/e:403(M+), 125(base) Example 98 3-(2-Methylphenyl)-5-(3-phenylpropionylamino)-4 (4-pyridyl)isoxazole 15 1H-NMR(CDCl 3 )8:8.38(dd,J=1.6Hz,4.6Hz,2H), 7.71-7.63(bs, 1H),7.38-7.18(m,9H),6.79(dd,J=1.6Hz,4.6Hz,2H), 3.03(t,J=7.3Hz,2H),2.80(t,J=7.3Hz,2H),2.05(s,3H) Mass,m/e:383(M+),9 1(base) 20 Example 99 3-(3-Methylphenyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole a) 5-Amino- 3-(3 -methylphenyl) -4-(4-pyridyl)isoxazole 25 1H-NMR(CDCl 3 )S:8.47(dd,J=1.5Hz,4.4Hz,2H),7.27(s,1H), 7.22(d,J=5.OHz,2H),7.14-7.11(m,1H), 7.03(dd,J=1.5Hz,4.4Hz,2H),5.06(bs,2H),2.31(s,3H) Mass,m/e:25 1 (M+),9 1 (base) 30 b) 3-(3-Methylphenyl)-5- (phenylacetylamino)-4-(4-pyridyl) isoxazole 1H-NMR(CDCl)8:8.44(dd,J=1.7Hz,4.6Hz,2H),7.68(bs,1H), 7.40-7.17(m,8H),7.04(d,J=6.9Hz,iH), 35 6.88(dd,J=1.7Hz,4.6Hz,2H),3.75(s,2H),2.29(s,3H) 54 Mass, m/e:369(M+),9 1 (base) Example 100 5-[(2-Chlorophenyl)acetylaminol-3-(3-methylphenyl)-4-(4-pyridyl) 5 isoxazole 1H-NMR(CDC1 3 )S:8.46(dd,J=1.7Hz,4.6Hz,2H),7.80(bs,1H), 7.44-7.41(m,1H),7.34-7.18(m,6H),7.06(d,J=6.9Hz,1H), 6.98(dd,J=1.7Hz,4.6Hz,2H),3.87(s,2H),2.30(s,3H) 10 Mass,m/e:403(M+), 125(base) Example 101 5-[(2-Fluorophenyl)acetylamino]-3-(3-methylphenyl)-4-(4-pyridyl) isoxazole 15 IH-NMR(CDCl 3 )8:8.45(dd,J=1.5Hz,4.6Hz,2H),7.96(bs,iH), 7.34-7.18(m,8H),6.96(dd,J=1.5Hz,4.6Hz,2H),3.77(s,2H), 2.30(s,3H) Mass,m/e:387(M+), 109(base) 20 Example 102 3-(3-Methylphenyl)-5-[(1-phenyl)cyclopropylcarboxyaminol-4 (4-pyridyl)isoxazole 25 1H-NMR(CDCl 3 )5:8.48(dd,J=1.7Hz,4.6Hz,2H), 7.46-7.37(m,6H),7.23-7.17(m,3H),7.04(d,J=6.9Hz,1H), 6.87(dd,J=1.7Hz,4.6Hz,2H),2.29(s,3H),1.69(q,J=3.8Hz,2H), 1.23(q,J=3.8Hz,2H) Mass,m/e:395(M+), 117(base) 30 Example 103 3-(3-Methylphenyl)-5-(3-phenylipropionylamino)-4-(4-pyridyl) isoxazole 35 1H-NMR(CDCl 3 )5:8.39(dd,J=1.5Hz,4.6Hz,2H),8.34(bs,1H), 55 7.30-7.16(m,8H), 7.03(d,J=7.3Hz, 1H), 6.94(dd,J=1.5Hz,4.6Hz,2H),3.00(t,J=7.3Hz,2H), 2.75(t,J=7.3Hz,2H),2.29(s,3H) Mass, m/e:383(M+),9 1 (base) 5 Example 104 5- [(2- Chlorophenvl)propionylaminol -3- (3- methylphenyl) -4- (4-pyridyl) isoxazole 10 1H-NMR(CDCl 3 )6:8.46(d,J=5.9Hz,2H),7.95(bs,1H), 7.35-7.31(m,1H),7.25-7.15(m,6H),7.06(d,J=6.8Hz,iH), 6.99(d,J=5.9Hz,2H),3.11(t,J=7.4Hz,2H),2.77(t,J=7.4Hz,2H), 2.30(s,3H) Mass,m/e:417(M+),25 1(base) 15 Example 105 5-[(3-Chlorophenvl)propionylaminol-3-(3-methylphenyl)-4-(4-pyridyl) isoxazole 20 lH-NMR(CDCl 3 )5:8.43(d,J=5.9Hz,2H),8.18(bs,1H), 7.23-7.18(m,6H),7.07-7.04(m,2H),6.97(d,J=5.9Hz,2H), 2.98(t,J=7.4Hz,2H),2.75(t,J=7.4Hz,2H),2.30(s,3H) Mass,m/e:417(M+), 251 (base) 25 Example 106 3-(3-Methylphenyl)-5-[(2-methylphenyl)propionvlamino]-4 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )S:8.44(d,J=6.OHz,2H),8.03(bs, 1H), 30 7.24-7.18(m,3H),7.15-7. 10(m,4H),7.05(d,J=7.03Hz, IH), 6.97(d,J=6.OHz,2H),2.99(t,J=7.6Hz,2H), 2.71(t,J=7.6Hz,2H), 2.30(s,3H),2.29(s,3H) Mass,m/e:397(M+), 105(base) 35 Example 107 56 3 -(3 -Methyiphenyl) -5- [(3 -methvlphenyl)propionylamino] -4 (4-pyridyl)isoxazole 1H-NMR(CDC1 3 ):8.45(dd,J=1 .4Hz,4.4Hz,2H), 7.79(bs, 1H), 5 7.24-7. 18(m, 3H), 7. 10-7.04(m, 5H), 6.95(dd,J=1.4Hz, 4.4Hz, 2H), 2.96(t,J=7.3Hz,2H), 2.73(t,J=7.3Hz,2H), 2.32(s, 3H), 2.30(s, 3H) Mass, m/e:39 7(M+), 105(base) Example 108 10 3- (4-Methylphenyl)-5-(phenylacetylamino) -4- (4-pvridyl)isoxazole a) 5-Amino-3(4-methlphenyl)-4(4pridl)isoxazole 1H-NMR(DMSO-d 6 )5:8.40(dd,J=1 .6Hz,4.5Hz,2H), 7.2 1(s,4H), 7.20(bs, 1H),7.01(dd,J1l.6Hz,4.5Hz,2H),2.33(hs,2H) 15 Mass, m/e:25 1(M+), 118(base) b) 3-(4-Methylp~henyl) 5-(phenvlacetylamino)-4-(4-pyridyl) isoxazole 20 1H-NMR(CDCl 3 )5:8.46(dd,J=1.5Hz,4.5Hz,2H),7.67(bs, 1H), 7.42-7.35(m,3H), 7.28-7.22(m,4H),7. 15(d,J=7. 7Hz,2H), 6.90(dd,J=1. 5Hz,4.4Hz, 2H), 3.76(s, 2H), 2. 36(s, 3H) Mass, m/e:369(MI), 9 1 (base) 25 Example 109 5- [(2-Chlorophenvl)acetylaminol -3- (4-methylphenyl)-4-(4-pyridyl) isoxazole 1H-NMR(DMSO-d 6 )5: 11.04(bs, 1H),8.50(dd,J=1.5Hz,4.4Hz,2H), 30 7A-4-7.34(m,2H),7.31-7.27(m,2H),7.24(s,4H), 7. 13(dd,J=1.5Hz,4.4Hz,2H),3.85(s,2H),2.33(s,3H) Mass,m/e:403(MI), 125(base) Example 110 35 3-(4-Methylphenyl) 5 -(phenyipropionylamino) -4- (4-pyridyl)isoxazole 57 1H-NMR(CDC1 3 )6:8.45(dd,J=1.7Hz,4.6Hz,2H),7.82(bs, 1H), 7.30-7.13(m,9H),6.95(dd,J=1.7Hz,4.6Hz,2H), 3.00(t,J=7.3Hz, 2H),2.75(t,J=7.3Hz,2H),2.35(s,3H) 5 Mass, m/e:383(M+),9 1(base) Example 111 3-(4-Ethylphenvl)-5-(p henvlacetylamino)-4-(4-pyridyl)isoxazole a) 5-Amino- 3 -(4-ethylphenyl) -4- (4-pyridyl)isoxazole 10 H-NMR(CDCl)6:8.52(dd,J=1.7Hz,4.4Hz,2H), 7.33(d,J=8.5Hz,2H),7.19(d,J=8.5Hz,2H), 7.07(dd,J=1.7Hz,4.4Hz,2H),4.83(bs,2H), 2.67(q,J=7.6Hz,2H),1.24(t,J=7.6Hz,3H) 15 Mass,m/e:265(M+), 132(base) b) 3-(4-Ethylphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 20 1H-NMR(CDC1 3 )5:8.46(dd,J=1.5Hz,4.4Hz,2H),7.57(bs, 1H), 7.40-7.33(m,3H),7.27-7.24(m,4H),7.16(d,J=8. lHz,2H), 6.90(dd,J=1.5Hz,4.4Hz,2H),3.75(s,2H),2.65(q,J=7.5Hz,2H), 1.22(t,J=7.5Hz,3H) Mass,m/e:383(M+),9 1 (base) 25 Example 112 5-(2-Chlorophenvlacetylamino)-3-(4-ethylphenyl)-4-(4-pyridyl) isoxazole 30 1H-NMR(CDCl 3 )8:8.47(dd,J=1.7Hz,4.4Hz,2H),7.71(bs,1H), 7.44-7.41(m,1H),7.33-7.26(m,5H),7.16(d,J=8.lHz,2H), 6.99(dd,J=1.7Hz,4.4Hz,2H),3.84(s,2H),2.65(q,J=7.3Hz,2H), 1.22(t,J=7.3Hz,3H) Mass,m/e:417(M+), 125(base) 35 58 Example 113 3-(4-Ethylphenyl)-5-(3-phenylpropionylamino)-4(4-pridl)isoxazole IH-NM4R(CDC1 3 )5:8.45(dd,J=1.5Hz,4.4Hz,2H), 7.84(bs, LH), 5 7.30-7.15(m,9H),6.96(dd,J=1.5Hz,4.4Hz,2H), 3.O(t,J=7.3Hz,2H), 2.75(t,J=7.3Hz,2H), 2.65(q,J= 7.7Hz,2H), 1.22(t,J=7.7Hz,3H) Mass, m/e:39 7(M+), 9 1 (base) 10 Example 114 3-(2-Fluoro-5-methylphenyvl) 5-(phenylacetvlamino)-4-(4-pyridyl) isoxazole a) 5 -Amino- 3 (2 -fluoro- 5 -methylp henyl) -4- (4-pyridyl) isoxazole 15 1H-NMR(CDC1 3 )5:8.43(dd,J=1.7Hz,4.6Hz,2H), 7.28(dd,J=1.9Hz,6.5Hz, iR), 7.23-7.20(m, 1H), 6.98(dd,J=1.7Hz,4.6Hz,2H),6.93(t,J=8.8Hz, lH), 5. 11(bs,2H),2.33(s,3H) Mass, m/e:269(M+), 6 3(base) 20 b) 3-(2-Fluoro-5-methylphenyl)-5(phenlacetlamino)-4 (4-pyridyl)isoxazole IH-NMR(CDC1 3 )8:8.41(dd,J=1 .9Hz,4.6Hz,2H), 7.57(bs, 1H), 25 7.43-7.35(m,3H),7.29-7.27(m,3H),7.24-7.20(m, 1H), 6.89(dd,J=8.4Hz,9.2Hz, 1H),6.80(dd,J=1.5Hz,4.6Hz,2H), 3.77(s,2H),2.33(s,3H) Mass, m/e:387(M+),9 1(base) 30 Example 115 3-(2-Fluoro-5 -methyiphenvl) 5-(3-phenvipropionylamino) -4 (4-pyrid-vlisoxazole IH-NMR(CDC1 3 )5:8.36(d,J=5.9Hz,2H),8.25(bs, 1H), 35 7.30-7. 17(m,7H),6.90(d,J=9.3Hz, 1H),6.87(d,J=5.9Hz,2H), 59 3.01 (t,J=7.3Hz, 2H), 2.76(t,J=7.3Hz, 2H), 2.33(s, 3H) Mass, m/e:40 1(M+),9 1 (base) Example 116 5 5- [(2- Chlorophenyl)propionylaminol -3- (2-fluoro- 5- methylphen-vl) -4 (4--pyridyl)isoxazole 1H-NMR(CDCl 3 ):8.41(d,J=5.9Hz,2H),8.03(bs, 1H), 7.35-7.32(m, 1H),7.28(dd,J=1..7Hz,6.3Hz, 1H),7.25-7. 17(m,4H), 10 6.93-6.88(m,3H),3. 12(t,J=7.6Hz,2H),2.78(t,J=7.6Hz,2H), 2.34(s,3H) Mass, m/e 3 5 (M+), 269 (base) Example 117 15 5- [(3-Chlorophenyl)propionylamino] -3-(2-fluoro-5-methvlphenyl)-4 (4-pyridyl)isoxazole lH-NMR(CDCl 3 )5:8.41(d,J=5.8Hz,2H),8.07(bs, lH), 7.28(dd,J=1.7Hz,6.2Hz, 1H),7.23-7.19(m,4H),7.08-7.06(m, lH), 20 6.92-6.88(m,3H),2.99(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,2H), 2.33 (s, 3H) Mass, m/e :435(M+), 269(base) Example 118 25 3- (2-Fluoro-5-methylphenyl)-5 -[(2-methylphenyl)propionvlaminol-4 (4-pyridyl)isoxazole 'H-NMR(CDCl 3 )8:8.49(d,J=6.OHz,2H),7.70(bs, iH), 7.27(d,J=7.4Hz, 1H),7. 16-7. 1O(m,4H),7.08-7.04(m, iH), 30 6.98(d,J=6.OHz,2H),6. 95(t,J=8.6Hz, 1H),2.99(t,J=7.6Hz,2H), 2.71(t,J=7.6Hz,2H),2.29(s,3H),2.22(d,J=1.6Hz,3H) Mass, mle:415(M+), 105(base) Example 119 60 3-(2-Fluoro-5-methvlphenyl)-5- [(3-methvlphenyl)propionylamino] -4 (4-pyridyl)isoxazole 1H-NMR(CDCL 3 )8:8.39(d,J=6. lHz,2H), 7.99(bs, IH), 5 7.28(dd,J=2. lHz,6.8Hz, 1H), 7.23-7.20(m,1H),7.11-7.06(m,4H), 6.91(d,J=9.3Hz, 1H),6.87(d,J=6. lHz,2H),2.97(t,J=7.4Hz,2H), 2.74(t,J=7.4Hz, 2H), 2.3 3(s, 3H), 2.3 1 (s, 3H) Mass, m/e:415(MI), 105(base) 10 Example 120 3-(3- Fluoro-4-methyiphenyl) 5-(phenylacetylamino) -4- (4-pyridyl) isoxazole a) 5 -Amino- 3 -(3 -fluoro- 4- methylp henyi) -4- (4 -pyridyl)isoxazole 15 1H-NMR(CDC1 3 ) 6 :8.51(dd,J=1.5Hz,4.6Hz,2H),7. 16(t,J=7.7Hz, 1H), 7.09(dd,J=1.9Hz, 10.4Hz, 1H), 7.06-7.04(m,3H),4.96(bs,2H), 2.28(s, 3H) Mass, m/e:269 (M'), 6 3(base) 20 b) 3-(3 -Fluoro-4-meth-vlphenyl) -5 -(phenylacetylamino) -4 pyridyl)isoxazole IH-NMR(CDCl 3 ):846(dd,J=1 .7Hz,4.6Hz,2H), 7.71(bs, 1H), 25 7.40-7.33(m,3H),7.26-724(m,2H),7. 13(t,J=77Hz, 1H), 7.04(dd,J=1.9Hz, 10Hz, 1H),6.98(dd,J=1.9Hz,8. 1Hz, 1H), 6.89(dd,J=1.7Hz, 4.6Hz,2H), 3. 75(s, 2H),2.27(d,J=1.9Hz, 3H) Mass, m/e:38 7(M+), 9 1 (base) 30 Example 121 5- [(2- Chlorophenyl)acet-vlaminol -3- (3 -fluoro-4-methylphenyl) 4- (4-pvridyl)isoxazole H-NMR(DMSO-d 6 )8: 11. 1(bs, 1H),8.53(dd,J=1.5Hz,4.6Hz,2H), 35 7.44-7.42(m, 1H),7.38-7.34(m,2H),7.32-7.28(m,2H), 61 7.17(dd,J=1.5Hz,4.6Hz,2H),7.15(dd,J=1.5Hz,8.8Hz, 1H), 7.08(dd,J=1.9Hz,8.OHz, 1H),3.86(s, 2H), 2.26(d,J=1.5Hz,3H) Mass,m/e:421(M+), 125(base) 5 Example 122 3-(3-Fluoro-4-methylphenyl)-5-(3-phenylpropionylamino)-4 (4-pvridyl)isoxazole lH-NMR(CDCl 3 )5:8.46(dd,J=1.7Hz,4.6Hz,2H),7.96(bs, 1H), 10 7.31-7.27(m,2H),7.24-7.17(m,3H),7.14(t,J=8.OHz,1H), 7.04(dd,J=1.5Hz, 10Hz, 1H),6.98(dd,J=1.5Hz,7.7Hz, 1H), 6.96(dd,J=1.7Hz,4.6Hz,2H),3.00(t,J=7.32Hz,2H), 2.75(t,J=7.32Hz,2H),2.27(d,J=1.5Hz,3H) Mass,m/e:401(M+),9 1(base) 15 Example 123 3-(4-Fluoro-3-methylphenyl)-5- (phenylacetylamino)-4-(4-pyridyl) isoxazole a) 5-Amino-3 -(4-fluoro- 3-methylphenyl) -4-(4-pyridyl)isoxazole 20 1H-NMR(CDCl 3 )6:8.54(dd,J=1.7Hz,4.4Hz,2H), 7.34-7.30(m,1H),7.16-7.12(m,1H),7.05(dd,J=1.7Hz,4.4Hz,2H), 6.98(t,J=9.1Hz,1H),4.84(s,2H),2.24(d,J=1.9Hz,3H) Mass,m/e:269(M+),63(base) 25 b) 3-(4-Fluoro-3-methylphenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )5:8.45(dd,J=1.5Hz,4.6Hz,2H),7.60(bs,1H), 30 7.42-7.33(m,3H),7.29-7.22(m,3H),7.08-7.03(m,1H), 6.94(t,J=9.1Hz,1H),6.89(dd,J=1.5Hz,4.6Hz,2H), 3.76(s,2H),2.22(d,J=1.9Hz,3H) Mass,m/e:387(M+),9 1(base) 35 Example 124 62 5- [(2-Chlorophenyl)acetylaminol -3-(4-fluoro- 3methylphenyl) 4- (4-pyridvl)isoxazole 'H-NMR(CDC1 3 )6:8.49(dd,J=1..7Hz,4.4Hz,2H), 7.63(bs, 1H), 5 7.45-7.42(m, 1H),7.35-7.26(m,4H),7.09-7.O5(m, 1H), 6.98(dd,J= 1.7Hz,4.4Hz,2H),6.95(t,J=8.9Hz, 1 H), 3.87(s,2H),2.22(d,J=1 I.9Hz, 3H) Mass,m/e:421(M+), 125(base) 10 Example 125 3-(4-Fluoro-3-methylphenyl)-5-(3-phenylpropionylamino)-4 (4-pyridyl)isoxazole 1H-NMR(CDC13)5:8.49(d,J=5.8Hz,2H), 7.69(s, 1H), 15 7.32-7. 16(m,5H),7.09-7.04(m, 1H),6.98-6.94(m,3H), 3.O1(t,J=7.4Hz,2H),2.77(t,J=7.4Hz,2H),2.23(s,3H) Mass,m/e:40 1(MI),9 1(base) Example 126 20 5- [(2-Chlorophenyl)propionylamino] -3-(4-fluoro- 5-methylphenyl) -4 (4-pyridyl)isoxazole 'H-NMR(CDCl 3 )5:8.49(dd,J=1 .5Hz,4.4Hz,2H),7. 79(bs, 1H), 7.35-7.32(m, 1H), 7.28(dd,J=1.7Hz,7.2Hz, 1H),7.24-7. 17(m,3H), 25 7.08-7.04(m,1H),6.99(dd,J=1.5Hz,4.4Hz,2H), 6.95(t,J=8.9Hz, 1H),3. 11(t,J=7.4Hz,2H),2.76(t,J=7.4Hz,2H), 2.22(d,J=1.7Hz,3H) Mass, m/e:435(MI), 269(base) 30 Example 127 5-[(3- Chlorophenyl)propionylamino] -3- (4-fluoro-5 -methvliphenyvl) -4 (4-pyridyl)isoxazole lH-NMR(CDCl 3 )8:8.52(d,J=5.8Hz,2H),7.53(bs, 1H), 35 7.29-7.27(m, 1H),7.21-7. 18(m,3H),7.09-7.05(m,2H), 63 6.98(d,J=5.8Hz, 2H),6.95(m, 1 H),2.98(t,J=7.4Hz, 2H), 2. 74(t,J=7.4Hz, 2H), 2.22(d,J=1.7Hz, 3H) Mass, m/e:43 5(MI), 269(base) 5 Example 128 3- (4- Fluoro- 5-methylphenyl) 5- [(2-methylphenyl)propionylaminoI -4 (4-pyridvl)isoxazole 1H-NMR(CDCl 3 )5:8.39(d,J=6.2Hz,2H),8. 17(bs, 1H), 10 7.29(dd,J=2.OHz,6.6Hz, 1H),7.23-7.2 1(m, 1H),7. 14-7. 12(m,4H), 6.92-6.88(m,3H),3.00(t,J=7.8Hz,2H),2.72(t,J=7.8Hz,2H), 2.33(s,3H),2.29(s,3H) Mass, m/e:415(M+), 105(base) 15 Examnie 129 3- (4- Fluoro- 5-methyip~henyl) -5- [(3 -methylphenyl)propionylaminoI -4 (4-pyrid-vl)isoxazole 1H-NMR(CDCl 3 )5:8.48(dd,J=1.3Hz,4.7Hz,2H),7.66(bs, 1H), 20 7.27(dd,J=1.7Hz,7.2Hz, 1H),7. 11-7.04(m,5H),6.97-6.92(m,3H), 2.96(t,J=7.4Hz,2H),2.72(t,J7.4Hz,2H),2.32(s,3H), 2.22(d,J=1.7Hz, 3H) Mass, m/e:41 5(M+), 105(base) 25 Example 130 3- (4- Chloro-3-methvlphenylh5 -(phenylacetylamino) -4-(4-pvridyl) isoxazole a) 5 -Amino - 3 -(4-chioro- 3-methyly hen-vl) -4- (4-pyridyl)isoxazole 30 IH-NMR(CDCl 3 )5:8.53(dd,J=1.5Hz,4.6Hz,2H), 7.35(d,J=1.9Hz, 1H),7.3 1(d,J=8. 1Hz, iH), 7. 10(dd,J=2.3Hz,8.5Hz, 1H),7.05(dd,J=1.5Hz,4.6Hz,2H), 4.87(bs,2H),2.34(s,3H) Mass, m/e:285(M+), 63(base) 35 64 b) 3-(4-Chloro-3-methylphenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole 1H-NMR(CDC1 3 ):8.48(dd,J=1.5Hz,4.2Hz,2H), 7.55(bs, iH), 5 7.42-7.25(m,7H),7.02(dd,J=1.9Hz,8. 1Hz, iH), 6.89(dd,J=1.5Hz,4.2Hz,2H),3.76(s,2H),2.32(s, 3H) Mass, m/e:403(M+),9 1 (base) Example 131 10 & (4-Chloro-3-methyiphenyi) 5- I2hlorophenyl)acetvlaminol -4 (4-pyridyl)isoxazole lH-NMR(CDC1 3 )5:8. 50(dd,Ji .5Hz,4.4Hz,2H), 7.69(bs, iH), 7.46-7.41(m, 1H), 7.35-7.26(m,5H), 7.03(dd,J=1.9Hz,8.5Hz, iH), 15 6.98(dd,J=1.5Hz,4.4Hz,2H),3.87(s,2H),2.30(s,3H) Mass, m/e:43 7(M+), 125(base) Example 132 3- (4-Chioro- 3-methyiphenyl) -5- (3-phen-vipropionylamino) -4 20 (4-pyrid-vlisoxazole 1H-NMR(CDCl 3 ):8.48(dd,J=1.6Hz,4.5Hz,2H),7.78(bs, 1H), 7.32-7. 16(m, 7H),7.02(dd,J=2. lHz,8.3Hz, 1H), 6.95(dd,J=1.6Hz,4.5Hz,2H),3.O 1(t,J=7.3Hz,2H), 25 2.75(t,J=7.3Hz,2H),2.34(s,3H) Mass, m/e:41 7(M+), 9 1 (base) Example 133 3-(4-Methoxy- 3- methylp henvl)-5 -(p henylacetylamino)- 4-(4-pyridyl) 30 isoxazole a) 5 -Amino- 3 -(4- methoxy- 3 -methylphenvl) -4- (4-p)vridvl)is oxazole IH-NMR(CDCl 3 )8:8.52(dd,J=1 .7Hz,4.6Hz,2H),7.25(m, 1H), 7. 15(dd,J=2.3Hz,8.5Hz, 1H),7.07(dd,J=1.7Hz,4.6Hz,2H), 35 6.77(d,J=8.5Hz, 1H),4.81(bs,2H),3.83(s,3H),2. 17(s,3H) 65 Mass,m/e:281(M+), 148(base) b) 3-(4-Methoxy-3-methylphenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole 5 'H-NMR(CDC1 3 )8:8.46(dd,J=1.6Hz,4.5Hz,2H),7.57(bs, 1H), 7.41-7.32(m,3H),7.28-7.23(m,2H),7.22-7.19(m, 1H), 7.06(dd,J=1.9Hz,8. 1Hz, 1H),6.9 1(dd,J=1.6Hz,4.5Hz,2H), 6.73(d,J=8.5Hz, 1H),3.82(s,3H),3.75(s,2H),2.14(s,3H) 10 Mass,m/e:399(M+),91(base) Example 134 5-[(2-Chlorophenvl)acetylamino]-3-(4-methoxy-3-methylphenyl)-4 (4-pyridyl)isoxazole 15 1H-NMR(CDCl 3 )8:8.48(dd,J=1.5Hz,4.4Hz,2H),7.65(bs, IH), 7.45-7.41(m, 1H),7.34-7.27(m,3H),7.23-7.21(m, iH), 7.08(dd,J=2.3Hz,8.7Hz, 1H),7.01(dd,J=1.5Hz,4.4Hz,2H), 6.74(d,J=8.7Hz, 1H),3.87(s,2H),3.82(s,3H),2.15(s,3H) 20 Mass,m/e:433(M+),125(base) Example 135 3-(4-Methoxy-3-methylphenyl)-5-(3-phenvlpropionylamino)-4 (4-pyridyl)isoxazole 25 1H-NMR(CDCl)8:8.46(d,J=5.9Hz,2H),7.74(bs,1H), 7.30-7.17(m,6H),7.06(dd,J=1.9Hz,8.4Hz,1H), 6.97(d,J=5.9Hz,2H),6.73(d,J=8.4Hz,lH), 3.82(s,3H),3.00(t,J=7.3Hz,2H),2.73(t,J=7.3Hz,2H), 30 2.14(s,3H) Mass,m/e:413 (M),9 1 (base) Example 136 3-(2,3-Dimethylphenyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole 35 a) 5-Amino- 3- (2,3-dimethylphenyl) -4-(4-pyridvl)isoxazole 66 1H-NMR(CDCl 3 )8:8.40(dd,J=1.7Hz,4.4Hz,2H),7.24-7.22(m, 1H), 7.16-7.13(m, 2H),6.88(dd,J=1.7Hz,4.4Hz,2H),4.98(bs,2H), 2.26(s,3H), 1.99(s,3H) 5 Mass,m/e:265(M+),77(base) b) 3-(2,3-Dimethylphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 10 IH-NMR(CDC1 3 )6:8.34(dd,J=1.5Hz,4.4Hz,2H),7.62(bs, 1H), 7.43-7.30(m,5H),7.22(d,J=7.3Hz, 1H),7.12(t,J=7.3Hz, 1H), 7.06(d,J=6.9Hz, 1H),6.70(dd,J=1.5Hz,4.4Hz,2H),3.80(s,2H), 2.23(s,3H), 1.89(s,3H) Mass,m/e:383(M+),9 1 (base) 15 Example 137 5-[(2-Chlorophenyl)acetylaminol-3-(2,3-dimethylphenyl)-4-(4-pyridyl) isoxazole 20 1H-NMR(CDCl 3 )S:8.35(dd,J=1.5Hz,4.6Hz,2H),8.01(bs,1H), 7.46-7.43(m,1H),7.37-7.35(m,1H),7.33-7.29(m,2H), 7.23(d,J=7.5Hz,1H),7.12(t,J=7.5Hz,1H),7.07(d,J=6.5Hz,1H), 6.81(dd,J=1.5Hz,4.6Hz,2H),3.91(s,2H),2.23(s,3H),1.90(s,3H) Mass,m/e:417(M+), 125(base) 25 Example 138 3-(2,3-Dimethylphenyl)-5-(3-phenylpropionylamino)-4-(4-pyridyl) isoxazole 30 1H-NMR(CDCl 3 )S:8.34(d,J=5.9Hz,2H),8.00(bs, 1H), 7.31-7.19(m,6H),7.12(t,J=7.3Hz, 1H),7.06(d,J=6.9Hz, 1H), 6.78(d,J=5.9Hz,2H),3.02(t,J=7.3Hz,2H),2.79(t,J=7.3Hz,2H), 2.23(s,3H), 1.9 1(s,3H) Mass,m/e:397(M+),9 1(base) 35 67 Example 139 5-[(2- Chlorophenyl)propionylamino] -3- (2,3-dimethylphenyl) -4 (4-pyridyl)isoxazole 5 1H-NMR(CDC 3 ):8.35(dd,J1.5Hz,4.6Hz2H),8.19(bs, 1H1), 7.35-7.3 1(m, 111), 7.27-7.09(m,6H),6.82(dd,J=1 .5Hz,4.6Hz,2H), 3. 12(t,J=7.6Hz,2H),2.80(t,J=7.6Hz,2H), 2.23(s,3H), 1 .91(s,3H) Mass, m/e:43 1 (M+), 265(base) 10 Example 140 5- [(3-Chlorophenyl)propionylamino] -3-(2. 3-dimethyiphenyl) -4 (4-pyridvl)isoxazole 1H-NMR(CDCl 3 )5:8.37(d,J=6.OHz,2H),7.92(bs, iH), 15 7.22-7.20(m,4H),7.13(t,J=7.4Hz, 1H), 7.1O-7.06(m,2H), 6.8 1(d,J=6.OHz, 2H), 3.00(t,J=7.4Hz,2H), 2. 78(t,J=7.4Hz,2H), 2.24(s, 3H), 1 .92(s,3H) Mass, m/e:43 1 (M+), 265 (base) 20 Example 141 3-(2,4-Dimethylphenyl) -5- [(2-meth-vlphenyl)propionylamino] -4 (4-pyridyl)isoxazole IH-NMR(CDCla)5:8.37(d,J=6.OHz,2H),7.82(bs, 1H1), 25 7.24(d,J=8.6Hz,2H), 7. 15-7.07(m,5H),6.81(d,J=6.OHz,2H), 3.02(t,J=7.6Hz, 2H), 2. 75(t,J=7.61z,211), 2.30(s, 3H), 2.24(s, 3H), 1 .92(s, 3H) Mass,m/e:411(M+), 105(base) 30 Example 142 3-(2, 4-Dimethyiphenyl) -5- [(3-methylphenyl)propionylaminol -4. (4-pyridyl)isoxazole IH-NMR(CDCl 3 )5:8.35(dd,J=1.7Hz,4.6Hz,2H),7.84(bs, 1H), 35 7.23(d,J=9.7Hz,1H),7.15-7.06(m,6H), 68 6.78(dd,J= 1. 7Hz,4.6Hz, 2H), 2.98(t,J=7.2Hz,2H), 2.76(t,J=7.2Hz,2H),2.32(s,3H),2.23(s,3H), 1.91(s,3H) Mass,m/e:41 (M+), 105(base) 5 Example 143 3-(2,5-Dimethylphenyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole a) 5-Amino- 3-(2,5- dimethylphenyl) -4- (4-pyridyl)isoxazole 1H-NMR(CDC1 3 )S:8.42(dd,J=1.7Hz,4.4Hz,2H),7.18-7.08(m,3H), 10 6.90(dd,J=1.7Hz,4.4Hz,2H),4.93(bs,2H),2.31(s,3H),2.01(s,3H) Mass,m/e:266(M+), 77(base) b) 3-(2,5-Dimethylphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 15 1H-NMR(CDCla)8:8.35(dd,J=1.7Hz,4.6Hz,2H),7.68(bs, 1H), 7.43-7.37(m,3H),7.31-7.30(m,2H),7.14(d,J=8.OHz, 1H), 7.08-7.04(m,2H),6.71(dd,J=1.7Hz,4.6Hz,2H),3.80(s,2H), 2.28(s,3H), 1.92(s,3H) 20 Mass,m/e:383(M+),91(base) Example 144 5-[(2-Chlorophenyl)acetylaminol-3-(2,5-dimethvlphenvl)-4 (4-pyridvl)isoxazole 25 IH-NMR(CDCl 3 ):8.38(d,J=5.9Hz,2H),7.66(bs,iH), 7.48-7.45(m,1H),7.39-7.36(m,1H),7.33-7.31(m,2H), 7.15(d,J=8.1Hz,1H),7.08-7.06(m,2H),6.83(d,J=5.9Hz,2H), 3.80(s,2H),2.28(s,3H),1.92(s,3H) 30 Mass,m/e:417(M+),125(base) Example 145 3-(2,5-Dimethylphenyl)-5-(3-phenylpropionylamino)-4-(4-pyridyl) isoxazole 35 69 1H-NMR(CDC1 3 )8:8.35(dd,J=1.5Hz,4.6Hz,2H),7.97(bs, 1H), 7.32-7.28(m,2H),7.24-7.19(m,3H), 7.15(d,J=7.7Hz, 1H), 7.09-7.05(m,2H),6.79(dd,J=1.5Hz,4.6Hz,2H), 3.02(t,J=7.3Hz,2H),2.78(t,J=7.3Hz,2H),2.29(s,3H), 1.94(s,3H) 5 Mass,m/e:397(M+),91(base) Example 146 3-(3,4-Dimethylphenyl)- 5 -(phenylacetylamino) -4- (4-pyridyl)isoxazole a) 5 -Amino-3 -(3,4- dimethylphenyl) -4- (4-pyridyl)isoxazole 10 1H-NMR(CDCl 3 ):8.52(dd,J=1.5Hz,4.5Hz,2H),7.18-7.03(m,5H), 4.83(bs,2H),2.28(s,3H),2.23(s,3H) Mass, m/e:265(M+), 77(base) 15 b) 3-(3,4-Dimethylphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 1H-NMR(CDC1 3 )5:8.46(dd,J=1.5Hz,4.6Hz,2H),7.51(bs,1H), 7.40-7.20(m,6H),7.07(d,J=7.7Hz,1H), 20 6.98(dd,J=1.5Hz,7.7Hz,1H),6.90(dd,J=1.5Hz,4.6Hz,2H), 3.76(s,2H),2.26(s,3H),2.20(s,3H) Mass,m/e:383(M+),9 1(base) Example 147 25 5-[2-(2-Fluorophenyl)acetylamino]-3-(3,4-dimethylphenyl)-4 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )8:8.48(dd,J=1.5Hz,4.6Hz,2H),7.65(bs,1H), 7.37-7.26(m,3H),7.21(m,1H),7.18-7.07(m,3H), 30 6.98(dd,J=1.5Hz,4.6Hz,2H),3.77(s,2H),2.26(s,3H), 2.21(s,3H) Mass,m/e:40 1 (M+), 109(base) Example 148 70 5- [2- (2- Chlorophenyl)acetylaminol -3- (3, 4-dimethyiphenyvl) -4 (4-pyridvl)isoxazole IH-NMR(CDCl 3 )8:8.48(d,J=6.2Hz,2H),7.45-7.43(m, 1H), 5 7.35-7.29(m,4H),7.21(bs,1IH),7.07(d,J=8. lHz, 1H), 7.O1-6.99(m,3H),3.87(s,2H),2.26(s,3H),2.21(s,3H) Mass, m/e:417(M+), 125(base) Example 149 10 5- [2- (2- Chloro-4-fluorophenyl)acetylaminol-3 -(3, 4-dimethyiphenyl) -4 (4-pvridvl)isoxazole LH-NMR(DMSO-d 6 )5: 11 .05(bs, 1H),8.53(dd,J=1.5Hz,4.4Hz,2H), 7.46-7.41(m,2H),7.22-7. 15(m,5H), 7.O1(dd,J=1.5Hz, 7.7Hz, lH), 15 3.86(s,2H),2.25(s,3H),2.20(s,3H) Mass, m/e:435(M+), 1 43(base) Example 150 3- (3.4-Dimethyip~henyl) 5-(3-phenvlpropionylamino) -4- (4-pyridyl) 20 isoxazole 1H-NMR(CDCl 3 )8:8.49(dd,J=1.5Hz,4.6Hz,2H), 7.58(bs, iH), 7.31-7. 17(m,6H),7.08-7.06(m, iH), 7.O(d,J=1.5Hz, 1H), 6.98(dd,J=1.5Hz, 4.6Hz,2H),3 .00(t,J=7.3Hz,2H), 25 2.75(t,J=7.3Hz,2H),2.26(s,3H),2.20(s,3H) Mass, m/e:397(M+),9 1 (base) Example 151 3 -(3, 5- Dim ethyiphenyl) -5 -(phenylacetylamino) -4 -(4-pyridyl)isoxazole 30 a) 5 -Amino- 3- (3,5 5-dimethylphenyl) -4- (4-y-vridyl)isoxazole 1H-NMR(CDC1 3 )5:8.51(dd,J=1 .5Hz,4.6Hz,2H),7.06-7.04(m,3H), 7.01(s,2H),4.84(bs,2H),2.26(s,6H) Mass, m/e: 265 (MI), 7 7 (base) 35 71 b) 3-(3, 5-Dimethvlphenyl)-5-(phenylacetylamino)-4-(4-pyridyl) isoxazole 'H-NMR(CDC1 3 )5:8.45(dd,J=1 .7Hz,4.6Hz,2H),7.55(bs, iH), 5 7.41-7.26(m,5H),7.04(s,1H),6.94(s,2H), 6.89(dd,J=1. 7Hz,4.6Hz,2H),3.75(s, 2H),2.23(s,6H) Mass, m/e: 383(M'), 9 1(base) Example 152 10 5- [(2- Chlorophenvl) acetylamino] .3-(3,5-dimethylphenyl) -4- (4-pyridyl) isoxazole

LH-NMR(CDCL

3 )5:8.47(dd,J=1 .5Hz,4.2Hz,2H),7.63(bs, iH), 7.44-7.42(m, iH), 7.33-7.28(m,3H), 7.04(s, 1H), 15 6.98(dd,J=1.5Hz,4.2Hz,2H),6.94(s,2H),3.87(s,2H),2.23(s,6H) Mass, m/e:417(M+), 125(base) Examvie 153 3- (3.5 -Dimethyiphenyl)- 5-(3-p~henvipropionylamino) -4- (4-pyridyl) 20 isoxazole 'H-NMR(CDC1 3 )5:8.46(dd,J=1. lHz,4.6Hz,2H),7.69(bs, iH), 7.31-7.1 7(m, 5H), 7.04(s, 1H),6.96-6.95(m,4H), 3.O(t,J=7.3Hz, 2H),2. 75(t,J=7. 3Hz, 2H), 2.23(s,6H) 25 Mass, m/e:397(M+),9 1(base) Example 154 5- [(2- Chlorophenyl)acetylamino] 3-(2,6-dimethyiphenyl) -4-(4-pyridyl) isoxazole 30 a) 5 -Amino- 3-(2. 6-dimethyiphenyl) -4-(4-p-yridyl)isoxazole 'H-NMR(DMSO-d 6 )5:8.28(dd,J=1 .9Hz,4.6Hz, 2H), 7.44(bs, 2H), 7.28(t,J=7.9Hz, 1H), 7. 14(d,J=7.9Hz,2H), 6.85(dd,J=1.9Hz,4.6Hz, 2H),2.03(s,6H) 35 Mass, m/e:265(M+), 77(base) 72 b) 5- [(2- Chlorophenyl)acetylamino] -3- (2,6 -dimethyilphenyl) -4 (4-pyridyl)isoxazole 5 lH-NMR(CDC13)5:8.5(dd,J=1.6Hz,4.5Hz,2H),7.73-7.63(m,3H), 7.49-7.46(m,2H),7.41-7.37(m,3H),7.29-7.27(m, 1H), 6.90(dd,J=1.6Hz,4.5Hz,2H),3.77(s,2H) Mass, m/e:423(MI),9 1 (base) 10 Example 155 5- (Phen-ylacetylamino) -4- (4-pyridyl) -3- (3-trifluoromethylphenvly isoxazole a) 5 -Amino- 4- (4- pyridyl) - 3 -(3 -trifluoromethylp henyl)isoxazole 15 1H-NMR(CDC1)6:8.57(dd,J=1.5Hz,4.6Hz,2H),7.79(s, iH), 7.70(d,J=77Hz, iH), 7.56(d,J=7.7Hz, 1H),7.50(t,J=7.7Hz, iH), 7.06(dd,J=1 .5Hz,4.6Hz,2H),4.93(bs, 2H) Mass, m/e: 30 5(M'), 173 (base) 20 b) 5 -(Phenylacetylam ino) -4- (4 -pyridyl) -3- (3 -trifluorom ethyl phenvl~isoxazole

IH-NMR(CDCI

3 )5:8.50(dd,J=1.6Hz,4.5Hz,2H), 773-7.63(m,3H), 7.49-7.46(m,2H),7.41-7.37(m,3H),7.29-7.27(m, 1H), 25 6.90(dd,J=1.6Hz,4.5Hz,2H),3.77(s, 2H) Mass, m/e:423(MI), 9 1 (base) Example 156 5- [(2-Chlorophenyl)acetylamino] -4-(4-pvyridyl)-3-(3-trifluoro 30 methylohenvlisoxazole 1H-NMR(DMSO-d 6 )5: 11. 17(bs, 1H),8.52(dd,J=1.6Hz,4.5Hz,2H), 7.88-7.84(m, 1H), 7.71-7.64(m,3H),7.45-7.40(m, 1H), 7.38-7.34(m, 1H),7.3 1-7.26(m,2H), 7, 17(dd,J=1.6Hz,4.5Hz,2H), 35 3.87(s,2H) 73 Mass,m/e:457(M+), 125(base) Example 157 5-[(2-Chlorophenyl)acetylamino]-3-(2-fluoro-3-trifluoromethylphenyl) 5 4-(4-pyridvl)isoxazole a) 5-Amino- 3 -(2-fluoro- 3 -trifluoromethylphenyl) -4- (4-pyridyl) isoxazole 1H-NMR(CDCl 3 )5:8.50(dd,J=1.5Hz,4.4Hz,2H), 10 7.71(m,2H),7.33(t,J=7.7Hz,1H),6.97(dd,J=1.5Hz,4.4Hz,2H), 4.98(bs,2H) Mass,m/e: 323(M+),63(base) b) 5-[(2-Chlorophenyl)acetylamino]-3-(2-fluoro-3-trifluoromethyl 15 phenyl)-4- (4-pyridyl)isoxazole IH-NMR(DMSO-d 6 )8:11.31(bs,1H),8.48(dd,J=1.5Hz,4.2Hz,2H), 7.98(t,J=6.9Hz,1H),7.91(t,J=7.7Hz,1H),7.58(t,J=7.7Hz,1H), 7.46-7.38(m,2H),7.33-7.28(m,2H),7.10(dd,J=1.5Hz,4.2Hz,2H), 20 3.92(s,2H) Mass,m/e:475(M+), 125(base) Example 158 3-(2-Fluoro-4-trifluoromethylphenyl)-5-(phenylacetylamino)-4 25 (4-pyridyl)- isoxazole a) 5-Amino- 3 -(2-fluoro-4-trifluoromethylphenyl) -4- (4-pyridyl) isoxazole 1H-NMR(CDCl 3 )8:8.48(dd,J=1.5Hz,4.6Hz,2H), 30 7.64(t,J=7.3Hz,lH),7.50(d,J=8.OHz,1H),7.34(d,J=9.6Hz,1H), 6.97(dd,J=1.5Hz,4.6Hz,2H),5.13(bs,2H) Mass,m/e:323(M+),63(base) b) 3-(2-Fluoro-4-trifluoromethylphenyl)-5-(phenylacetylamino)-4 35 (4-pyridyl)isoxazole 74 1H-NM4R(CDC1 3 ):8.45(dd,J=1 .5Hz,4.2Hz,2H), 7.63(t,J=7.3Hz, 1H),7.54(bs, 1H),7.5 1(d,J=9.25Hz, 1H), 7.39-7.38(m, 3H), 7.32- 7.27(m, 3H),6.79(dd,J=1 .5Hz, 4.2Hz, 2H), 5 3.78(s,2H) Mass,m/e:441 (M),9 1 (base) Example 159 5- [(2- Chlorophen-vl)acetylamino] -3- (2-fluoro-4trifluoromethylphenyl) 10 4-(4-pvridyl)isoxazole 'H-NMR(DMSO-d 6 )5: 11 .29(bs, 1H),8.49(dd,J=1.9Hz,4.6Hz,2H), 7.85-7.82(m,2H), 7.77(d,J=8.OHz, 1H),7.46-7.38(m,2H), 7.33-7.30(m,2H),7. 12(dd,J=1.9Hz,4.6Hz,2H),3.91(s,2H) 15 Mass, m/e: 475(M±), 125(base) Example 160 3- (2- Fluoro- 5trifluoromethylphen-vl) -5- (phenylacetylamino) -4 (4-pyridvl~isoxazole 20 a) 5 -Amino- 3 - (2 -fluoro- 5 -trifluoromethylphenyl) -4- (4-pyridyl) isoxazole 1H-NMR(CDC1 3 )5:8.5 i(dd,J=1.5Hz,4.6Hz,2H), 7.85(dd,J=2.3Hz,6. 1Hz, iH), 7.75-7.7 1(m, 1H), 25 7. 18(t,J=8.8Hz, 1H),6.98(dd,J=1.5Hz,4.6Hz,2H),4.97(bs,2H) Mass, m/e:323(M+), 63(base) b) 3-(2- Fluoro-5-trifluoromethylphenyl) -5- (phenylacetylamino) 4- (4-pyridvl~isoxazole 30 LH-NMR(CDCl 3 )8:8.45(dd,J=1. 7Hz,4.6Hz,2H), 7.83(dd,J=2.3Hz,6, 1Hz, 1H),7. 75-7.71(m, 1H),7.53(bs, 1H), 7.43-7.23(m, 5H), 7. 15(t,J=9.3Hz, iH), 6.80(dd,J=1.7Hz,4.6Hz,2H),3.78(s,2H) 35 Mass,m/e:441(M'),91(base) 75 Example 161 5-[(2-Chlorophenvl)acetylamino]-3-(2-fluoro-5-trifluoromethylphenyl) 4-(4-pyridyl)isoxazole 5 1H-NMR(CDCl 3 )6:8.45(dd,J=1.5Hz,4.6Hz,2H), 7.83(dd,J=2.3Hz,5.8Hz,2H),7.75-7.71(m,1H),7.46-7.44(m,1H), 7.36-7.28(m,3H),7.15(t,J=8.8Hz,iH), 6.90(dd,J=1.5Hz,4.6Hz,2H),3.89(s,2H) 10 Mass,m/e:475(M+), 125(base) Example 162 3-(2-Fluoro-5-trifluoromethylphenyl)-5-(3-phenylpropionylamino)-4 (4-pyridyl)isoxazole 15 1H-NMR(CDCl 3 )S:8.40(dd,J=1.6Hz,4.4Hz,2H), 8.19(bs,1H),7.82(dd,J=2.3Hz,6.1Hz,lH),7.75-7.71(m,1H), 7.32-7.13(m,6H),6.86(dd,J=1.6Hz,4.4Hz,2H), 3.01(t,J=7.3Hz,2H),2.77(t,J=7.3Hz,2H) 20 Mass,m/e:455(M+),91(base) Example 163 3-(3-(Fluoro-5-trifluoromethylphenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole 25 a) 5-Amino- 3- (3 -fluoro- 5 -trifluoromethylphenyl) -4- (4-pyridyl) isoxazole 1H-NMR(CDCl)8:8.53(dd,J=1.5Hz,4.4Hz,2H), 7.52(s,1H),7.38(d,J=8.OHz,1H),7.29(d,J=8.8Hz,1H), 30 7.04(dd,J=1.5Hz,4.4Hz,2H),5.15(bs,2H) Mass, m/e:323(M+), 63(base) b) 3-(3-(Fluoro-5-trifluoromethylphenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole 35 76 1H-NMR(CDC1 3 )8:8.51(m,2H),7.71(bs, 1H),7.47(s, 1H), 7.41-7.37(m,4H),7.26-7.23(m,3H),6.90(dd,J=1.5Hz,4.2Hz,2H), 3.75(s,2H) Mass,m/e:441(M+),9 1 (base) 5 Example 164 5- [(2-Chlorophenyl)acetylamino] -3-(3-fluoro-5-trifluoromethylphenvl) 4-(4-pyridyl)isoxazole 10 IH-NMR(CDCl 3 )5:8.52(d,J=5.7Hz,2H),7.83(bs, 1H),7.48(s, IH), 7.44-7.42(m, 1H), 7.38(d,J=8.OHz, 1H),7.34-7.28(m,3H), 7.25(d,J=5.4Hz, 1H),6.99(d,J=5.7Hz,2H),3.87(s,2H) Mass,m/e:475(M+), 125(base) 15 Example 165 3-(3-Fluoro-5-trifluoromethylphenyl)-5-(3-phenylpropionylamino)-4 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )6:8.49(dd,J=1.7Hz,4.5Hz,2H),7.98(bs, 1H), 20 7.46(s, 1H),7.38(d,J=8.OHz, 1H),7.31-7.17(m,6H), 6.95(dd,J=1.7Hz,4.5Hz,2H),3.01 (q,J=7.3Hz,2H), 2.76(q,J=7.3Hz,2H) Mass,m/e:455(M+),9 1 (base) 25 Example 166 3-(4-Fluoro-3-trifluoromethylphenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole a) 5 -Amino-3 -(4-fluoro- 3 -trifluoromethylphenyl) -4- (4-pyridyl) isoxazole 30 1H-NMR(CDC1 3 )S:8.57(dd,J=1.5Hz,4.2Hz,2H), 7.79(dd,J=2.lHz,6.7Hz,1H),7.56-7.51(m,1H), 7.19(t,J=9.2Hz,1H),7.05(dd,J=1.5Hz,4.2Hz,2H), 4.92(bs,2H) 35 Mass,m/e:323(M+,base) 77 b) 3-(4- Fluoro- 3-trifluoromethyiphenvi)-5-(phenylacetylamino)- 4 (4-pyridyl)isoxazole 5 lH-NMR(CDC1 3 )6:8.52(dd,J=1 .7Hz,4.4Hz,2H), 7.73(dd,J=2. lHz,6.7Hz, 1H),7.54(bs, 1H),7.49-7.44(m, 1H), 7.43-7.36(m,3H),7.28-7.24(m,2H),7. 17(t,J=9.2Hz, 1H), 6.90(dd,J=1. 7Hz,4.4Hz,2H),3. 76(s, 2H) Mass,m/e:44 1 (MI),9 1 (base) 10 Example 167 5- [(2- Chloropheny1) acetylamino] -3- (4-fluoro- 3-trifluoromethyiphenyl) 4- (4-pyridvl)isoxazole 15 1H-NMR(CDC1 3 ):8.53(dd,J=1 .7Hz,4.4Hz,2H), 7.74(dd,J=2. lHz,6.7Hz, 1H),7.69(bs, 1H), 7.5 1-7.42(m,2H), 7.35-7.28(m, 3H), 7.1 7(t,J=9.2Hz, lH), 6.99(dd,J=1. 7Hz,4.4Hz,2H),3.87(s,2H) Mass, m/e:475 (M'), 125(base) 20 Example 168 3-(3-Fluoro-5-trifluoromethylphenyl)-5-(3-phenylpropionylamino)-4 (4-pyridyl)isoxazole 25 lH-NMR(CDC1 3 )5:8.52(dd,J=1 .6Hz,4.5Hz,2H), 7.76-7.71(m,2H), 7.50-7.44(m, 1H), 7.32-7.27(m,2H), 7.25-7. 16(m,3H),6.96(dd,J=1.6Hz,4.5Hz,2H), 3.01 (t,J=7. 3Hz, 2H), 2.75(t,J=7. 3H-z,2H) Mass, m/e:455(M+), 9 1 (base) 30 Example 169 3 -(4- Chioro- 3-trifluorophenyl) -5 -(phenylacetylamino) -4- (4-pyridyl) isoxazole a) 5 -Amino- 3 -(4- chloro- 3-trifluorophenyl) -4- (pyrid-yl)isoxazl 35 78 1H-NMR(CDC1 3 )8:8.58(dd,J=1.5Hz,4.5Hz,2H), 7.85(m, IH), 7.47(m, 2H), 7.05(dd,J=1.5Hz,4.5Hz, 2H), 4.90(bs,2H) Mass,m/e:339(M+),63(base) 5 b) 3-(4-Chloro-3-trifluorophenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole 1H-NMR(CDCl 3 )8:8.53(dd,J=1.5Hz,4.4Hz,2H), 10 7.80(d,J=1.9Hz,1H),7.51(bs,1H),7.47(d,J=8.5Hz,1H), 7.40-7.35(m,4H),7.27-7.24(m,2H),6.90(dd,J=1.5Hz,4.4Hz,2H), 3.76(s,2H) Mass,m/e:457(M+),9 1 (base) 15 Example 170 3-(4-Chloro-3-trifluorophenyl)-5-[2-(2-chlorophenyl)acetylaminol-4 (4-pyridyl)isoxazole lH-NMR(CDC1 3 )8:8.54(dd,J=1.5Hz,4.6Hz,2H), 20 7.81(d,J=1.9Hz,1H),7.60(bs,1H),7.49-7.39(m,3H), 7.35-7.29(m,3H),6.99(dd,J=1.5Hz,4.6Hz,2H),3.87(s,2H) Mass,m/e:491 (M+), 125(base) Example 171 25 3-(4-Chloro-3-trifluorophenyl)-5-(3-phenylpropionylamino)-4 (4-pyridyl)isoxazole LH-NMR(CDC1 3 )S:8.53(dd,J=1.5Hz,4.2Hz,2H), 7.80(d,J=1.9Hz,1H),7.75(bs,1H),7.48-7.37(m,2H), 30 7.32-7.17(m,5H),6.96(dd,J=1.5Hz,4.2Hz,2H), 3.00(t,J=7.3Hz,2H), 2.75(t,J=7.3Hz,2H) Mass,m/e:471(M+),9 1(base) Example 172 35 3-(4-Biphenyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole 79 a) 5-Amino-3-(4-biphenyl)-4-(4-pyridyl)isoxazole 1H-NMR(CDCl 3 )6:8.56(dd,J=1.5Hz,4.4Hz,2H), 7.63-7.58(m,4H),7.52-7.42(m,4H),7.39-7.33(m,iH), 5 7.11(dd,J=1.5Hz,4.4Hz,2H),4.82(bs,2H) Mass,m/e:313(M+), 152(base) b) 3-(4-Biphenyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole 10 1H-NMR(CDCl 3 )8:8.48(dd,J=1.7Hz,4.6Hz,2H),7.61(bs, IH), 7.58-7.56(m,4H),7.45-7.34(m,9H),7.28-7.25(m, 1H), 6.94(dd,J=1.7Hz,4.6Hz,2H),3.77(s,2H) Mass,m/e:43 1(M+),9 1(base) 15 Example 173 5- [(2-Chlorophenyl)acetylamino) -3-(4-biphenyl)-4-(4-pyridyl) isoxazole lH-NMR(CDCl 3 )6:8.50(dd,J=1.7Hz,4.6Hz,2H), 7.66(bs, 1H), 20 7.57(d,J=8.lHz,4H),7.45-7.41(m,5H),7.38-7.28(m,4H), 7.04(dd,J=1.7Hz,4.6Hz,2H),3.88(s,2H) Mass,m/e:465(M+), 179(base) Example 174 25 3-(4-Biphenyl)-5-(3 -phenylpropionylamino)-4-(4-pyridyl)isoxazole 1H-NMR(DMSO-ds)6:10.84(bs,1H),8.52(dd,J=1.5Hz,4.2Hz,2H), 7.75(d,J=8.5Hz,2H),7.71(d,J=7.3Hz,2H),7.50-7.44(m,4H), 7.39(t,J=7.3Hz,1H),7.31-7.27(m,2H),7.23-7.20(m,3H), 30 7.12(dd,J=1.5Hz,4.2Hz,2H),2.87(t,J=7.5Hz,2H), 2.68(t,J=7.5Hz,2H) Mass, m/e:445(M+), 91 (base) Example 175 35 3-(1-Naphthyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole 80 a) 5-Amino-3-(1 -naphthyl)-4-(4-pyridyl)isoxazole LH-NMR(CDC1 3 )5:8.30(dd,J=1.5Hz,4.6Hz,2H),7.97-7.92(m, 1H), 7.87(d,J=7.7Hz, 1H),7.83(d,J=8.5Hz, 1H),7.51-7.44(m,3H), 5 7.39-7.35(m, 1H),6.83(dd,J=1.5Hz,4.6Hz,2H),5.02(bs,2H) Mass,m/e:287(M+,base) b) 3-(1-Naphthyl)-5-(phenylacetylamino)-4-(4-pyridvl)isoxazole 10 lH-NMR(CDCl 3 )5:8.22(dd,J=1.9Hz,4.6Hz,2H), 7.94(d,J=8. 1Hz, 1H),7.86(d,J=8. 1Hz, 1H),7.84(bs, 1H), 7.67(d,J=8.5Hz, 1H),7.49-7.29(m,9H), 6.65(dd,J=1.9Hz,4.6Hz,2H),3.82(s,2H) Mass, m/e:405(M+),91 (base) 15 Example 176 5-[(2-Chlorophenvl)acetylamino]-3-(1-naphthyl)-4-(4-pyridyl) isoxazole 20 1H-NMR(CDCla):8.25(dd,J=1.5Hz,4.6Hz,2H), 7.94(d,J=8.1Hz,1H),7.86(bs,1H),7.86(d,J=8.1Hz,1H), 7.70(d,J=9.2Hz,1H),7.48-7.30(m,8H), 6.77(dd,J=1.5Hz,4.6Hz,2H),3.94(s,2H) Mass,m/e:439(M+), 125(base) 25 Example 177 3- (1 -(Naphthyl)- 5-(3 -phenylpropionylamino) -4-(4-pyridyl)isoxazole 'H-NMR(CDCl 3 )5:8.23(dd,J=1.5Hz,4.6Hz,2H),8.05(bs, 1H), 30 7.92(d,J=8.lHz, 1H),7.86(d,J=8. lHz,1H),7.72(d,J=8. 1Hz, 1H), 7.46(t,J=6.9Hz,2H),7.41-7.20(m,8H), 6.73(dd,J=1.5Hz,4.6Hz, 1H),3.04(t,J=7.3Hz,2H), 2.81(t,J=7.3Hz,2H) Mass,m/e:419(M+),9 1 (base) 35 81 Example 178 3-(2-Naphthyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole a) 5-Amino- 3- (2-naphthyl) -4- (4-pyridyl) isoxazole 5 1H-NMR(CDCl 3 )8:8.52(dd,J=1.6Hz,4.5Hz,2H),7.97(s,1H), 7.87-7.76(m,3H),7.56-7.44(m,3H),7.08(dd,J=1.6Hz,4.5Hz,2H), 4.87(bs,2H) Mass,m/e:287(M+), 154(base) 10 b) 3-(2-Naphthyl)-5-(phenylacetylamino)-4-(4-pyridyl)isoxazole 1H-NMR(CDC1 3 )5:8.46(dd,J=1.6Hz,4.3Hz,2H), 7.90-7.72(m,4H),7.63(bs,1H),7.55-7.46(m,2H), 7.43-7.34(m,4H),7.30-7.26(m,2H),6.92(dd,J=1.6Hz,4.3Hz,2H), 15 3.78(s,2H) Mass,m/e:405(M+),9 1(base) Example 179 5-[2-(2-Chlorophenyl)acetylamino]-3-(2-naphthyl)-4-(4-pyridyl) 20 isoxazole 1H-NMR(CDCl 3 ):8.47(dd,J=1.6Hz,4.5Hz,2H),7.90(bs,iH), 7.85-7.73(m,4H),7.55-7.27(m,7H),7.02(dd,J=1.6Hz,4.5Hz,2H), 3.89(s,2H) 25 Mass,m/e:439(M+), 153(base) Example 180 3-(2-Naphthyl)-5-(3-phenylpropionylamino)-4-(4-pyridyl)isoxazole 30 . H-NMR(CDC1 3 )8:8.45(dd,J=1.5Hz,4.6Hz,2H),7.92(bs,1H), 7.88(s,1H),7.81(dd,J=8.2Hz,14.8Hz,2H),7.73(d,J=8.2Hz,1H), 7.56-7.46(m,2H),7.39(dd,J=1.9Hz,8.5Hz,1H),7.32-7.17(m,4H), 6.99(dd,J=1.5Hz,4.6Hz,2H),3.02(t,J=7.3Hz,2H), 2.78(t,J=7.3Hz,2H) 35 Mass,m/e:419(M+),91(base) 82 Example 181 3-[2-(5 -Methylfuryl) -5-phenylacetylamino-4- (4-pvridyl)isoxazole a) 5 -Amino- 3 - [2 - (5 -methylfuryl)] -4- (4 -pyridyl) isoxazole 5 1H-NMR(CDCl 3 )5:8.6 1(dd,J=4.2Hz,5.8Hz,2H), 7.26(dd,J=1.7Hz,4.2Hz,2H),6.46(d,J=3.5Hz, iH), 6.02(dd,J=3.5Hz,4.2Hz, 1H),4.82-4. 72(bs,2H),2.30(s,3H) Mass, m/e:24 1(M+), 118(base) 10 b) 3-[2-(5-Methylfuryl)] -5-phenylacetylamino-4- (4-pyridvi) isoxazole 1H-NMR(CDCl 3 ):8.57(dd,J=4.6Hz,6.2Hz,2H), 15 7.41-7.3 1(m,4H),7.24-7.20(m,2H),7. 10(dd,J=4.6Hz,6.2Hz,2H), 6.35(d,J=3.5Hz, 1H),6.01-5.98(m, 1H),3.72(s,2H),2.28(s,3H) Mass, m/e:359(MI),9 1 (base) Example 182 20 5- [2- (2- Chlorophenyl)acetylamino] -3- [2- (5-methylfuryl)] -4-(4-pyridyl) isoxazole 1H-NMR(CDC1 3 )8:8. 58(dd,J=4.6Hz,6.2Hz, 2H), 7.53-7.50(bs, 1H),7.44-7.40(m, 1H),7.33-7.24(m,3H), 25 7. 17(dd,J=4.6Hz,6.2Hz,2H),6.36(d,J=3. 1Hz, iH), 6.02-5.98(m, 1H),3.83(s,2H),2.28(s,3H) Mass, m/e:393(M+), 125(base) Example 183 30 3- [2- (5-Methylfuryl)] -5-(3-phenylpropionylamino) -4-(4-pvyrid-vl) isoxazole 1H-NMR(CDCl 3 )8:8.58(dd,J=4.4Hz,6.2Hz, 2H), 7.56-7.50(bs, 1H),7.30-7. 19(m,5H),7. 15(dd,J=4.4Hz,6.2Hz, 2H), 35 6.34(d,J=3.5Hz, 1H),6.O1-5.98(m, 1H),2.97(t,J=7.4Hz,2H), 83 2.7 1(t,J=7.4Hz, 2H), 2.28(s,3H) Mass,m/e:373(M+),9 1(base) Example 184 5 3-(4-Fluorophenyl)-4-[4-(2-fluoropyridyl)]-5-(phenylacetylamino) isoxazole a) 4-(2-Fluoropyridyl)acetonitrile A mixture of 1.0 g of 2-fluoro-4-methylpyridine and 2.2 g of t-butoxybisdimethylaminomethane was stirred at 180*C for 18 hours. 10 The reaction solution was cooled, from which t-butoxybisdimethyl aminomethane was distilled off under reduced pressure, to provide a dark brown, oily residue. To the residue, 10 mL of water and 2.5 g of hydroxylamine-O-sulfonic acid were added and stirred at room temperature for 30 minutes. The reaction solution was rendered 15 basic by addition of saturated aqueous sodium hydrogencarbonate solution under cooling with ice, and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous magnesium sulfate, and removed of the solvent by reduced pressure distillation to provide 0.93 g (yield, 76%) of the title compound as pale yellow 20 crystals. 1H-NMR(CDCl 3 )5:8.26(d,J=5.OHz, 1H),7.20-7.17(m, 1H), 6.97-6.95(m,1H),3.81(s,2H) Mass,m/e: 136(M+,base) 25 b) 5-Amino- 3 -(4-fluorophenyl) -4- [4- (2-fluoropyridyl) isoxazole In 5 ml of ethanol, 0.132 g of sodium ethoxide was dissolved and into which a solution of 0.39 g of 2-fluoro-4-pyridylacetonitrile in 5 mL of THF was dropped, followed by 20 minutes' stirring under 30 cooling with ice. Then a solution of 0.50 g of 4-fluorobenz hydroxymoyl chloride in 5 mL of ethanol was added dropwise under cooling with ice, and thereafter stirred at room temperature for 2 hours. After distilling the solvent off from the reaction solution under reduced pressure, water was added, and the precipitated 35 residue was recovered by filtration, washed with water and dried 84 under reduced pressure. The residue was purified on 20 g silica gel column chromatography (eluent, chloroform -> chloroform: methanol = 100 : 1) to provide 0.597 g (yield: 76%) of the title compound as light brown crystals. 5 1H-NMR(DMSO-d 6 )5:8.05(d,J=5.4Hz,1H),7.43-7.37(m,4H), 7.30-7.24(m,2H),6.86-6.84(m,1H),6.78(bs,1H) Mass,m/e:273(M+), 123(base) 10 c) 3-(4-Fluorophenyl)-4-[4-(2-fluoropyridyl)]-5-(phenylacetyl amino)isoxazole In 5 mL of THF, 0.180 g of imidazole and 0.43 mL of DBU were dissolved, and while stirring it under cooling with ice, 0.24 mL of phenylacetyl chloride was dropped thereinto, followed by 10 minutes' 15 stirring at room temperature. Then a solution of 0.120 g of 5-amino- 3-(4-fluorophenyl) -4- [4- (2-fluoropyridyl)] isoxazole in 4 mL of THF was added dropwise, followed by 8 hours' stirring at room temperature. Distilling the solvent off from the reaction solution under reduced pressure , water was added to the residue, followed by 20 extraction with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. The resultant residue was purified on 20 g silica gel column chromatography (eluent, chloroform -+ chloroform: methanol = 50 : 1) and recrystallized from 25 ether-hexane to provide 0.132 g (yield: 77%) of the title compound as colorless crystals. IH-NMR(CDCl 3 )5:8.10(d,J=5.4Hz,1H),7.50-7.24(m,8H), 7.10-7.04(m,2H),6.89(dt,J=1.5Hz,5.4Hz,1H),6.57(bs,1H), 30 3.77(s,2H) Mass,m/e:391(M+),9 1(base) Example 185 5-[2-(2-Chlorophenyl)acetylaminol-3-(4-fluorophenyl)-4-[4-(2 35 fluoropyridyl)lisoxazole 85 The title compound was synthesized in the manner similar to Example 184. 1H-NMR(CDCl 3 )5:8.11(d,J=5.4Hz,1H),7.53(bs,1H), 5 7.47-7.45(m,1H),7.37-7.30(m,5H),7.09-7.04(m,2H), 6.85(dt,J=1.5Hz,5.4Hz,1H),6.63(bs,1H),3.87(s,2H) Mass,m/e:425(M+), 125(base) Example 186 10 4-[4-(2-Bromopyridyl)]-3-(4-fluorophenyl)-5-(phenylacetylamino) isoxazole a) 4-(2-Bromopyridyl)acetonitrile A mixture of 1.5 g of 2-bromo-4-methylpyridine and 3.0 g of t-butoxybisdimethylaminomethane was stirred at 110*C for 15 hours. 15 The reaction solution was cooled, and from which t-butoxybisdimethylaminomethane was distilled off under reduced pressure to provide dark brown oily residue. To this residue 20 mL of water and 2.5 g of hydroxylamine-O-sulfonic acid were added and stirred at room temperature for an hour. The crystals precipitated in 20 the reaction solution were recovered by filtration, washed with water, and dried to provide 1.06 g (yield: 62%) of the title compound as brown crystals. 1H-NMR(CDCl 3 )5:8.40(d,J=5.OHz, 1H), 25 7.5 1(dd,J=0.8Hz, 1.5Hz, 1H),7.27-7.24(m, 1H),3.75(s,2H) Mass,m/e:196(M+), 117(base) b) 5-Amino-4- [4-(2-bromopyridyl)] -3-(4-fluorophenyl)isoxazole In 5 mL of ethanol, 0.380 g of sodium ethoxide was dissolved, 30 and into which a solution of 1.0 g of 2-bromo-4-pyridylacetonitrile in 10 mL of THF was dropped, followed by 30 minutes' stirring at room temperature. Then a solution of 0.881 g of 4-fluorobenzhydroxymoyl chloride in 5 mL of ethanol was dropped, followed by 5 hours' stirring at room temperature. After distilling the solvent off from the 35 reaction solution under reduced pressure, saturated aqueous 86 ammonium chloride solution was added and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous magnesium sulfate, from which the solvent was distilled off under reduced pressure The resultant residue was purified on 50 g silica 5 gel column chromatography (eluent, chloroform -> chloroform: methanol = 50 : 1) to provide 0.77 g (yield: 45%) of the title compound as reddish dark brown crystals. 1H-NMR(CDCl 3 )5:8.26(d,J=5.0Hz,1H),7.41-7.38(m,2H), 10 7.28(d,J=1.2Hz,lH),7.11-7.07(m,2H), 6.93(dd,J=1.5Hz,5.OHz,1H),4.91(bs,2H) Mass,m/e:335(M+), 123(base) c) 4-[4-(2-Bromopyridyl)]-3-(4-fluorophenyl)-5- (phenylacetyl 15 amino)isoxazole In 3 mL of THF, 0.124 g of imidazole and 0.54 mL of DBU were dissolved, to which 0.23 mL of phenylacetyl chloride was added dropwise under stirring and cooling with ice, followed by 10 minutes' stirring at room temperature. Then a solution of 0.200 g of 20 5-amino- 3- (4-fluorophenyl)-4- [4-(2-bromopyridyl)] isoxazole in 10 mL of THF was added dropwise, followed by 17 hours' stirring at room temperature. Distilling the solvent off from the reaction solution under reduced pressure, water was added to the residue and extracted with methylene chloride. The organic layer was dried over 25 anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. The resultant residue was purified on 10 g silica gel column chromatography (eluent, chloroform -> chloroform: methanol = 100 : 1) to provide 0.260 g (yield: 96%) of the title compound as pale yellow crystals. 30 1H-NMR(CDCl 3 )5:8.24(d,J=5.OHz, 1H),7.44-7.26(m,8H), 7.17(bs, 1H),7.10-7.03(m,2H),6.84(dd,J=1.5Hz,5.OHz,1H), 3.76(s,2H) Mass,m/e:453(M+),9 1(base) 35 87 Example 187 3-(4-Fluorophenyl)-4- [4-(2-methoxypyridyl)] -5-(phenylacetylamino) isoxazole a) 5-Amino- 3 -(4-fluorophenyl) -4-4- (2-methoxvpvridvl)l isoxazole 5 A mixture of 0.100 g of 5-amino-3-(4-fluorophenyl)-4-[4-(2 fluoropyridyl)]isoxazole, 3 mL of methanol and 0.2 mL of methanol solution containing 28% NaOMe was heated and refluxed under atmosphere of argon for 4.5 hours. After termination of the reaction, the reaction solution was distilled off under reduced pressure. The 10 residue was dissolved in chloroform and washed with saturated aqueous ammonium chloride solution. The organic layer was dried over magnesium sulfate, and from which the solvent was distilled off under reduced pressure. The resultant residue was purified on 5 g silica gel column chromatography (eluent, chloroform: methanol= 15 50 : 1) to provide 0.162 g (yield: 97%) of the title compound. 1H-NMR(CDCl 3 )8:8.08(d,J=5.OHz,1H),7.47-7.41(m,2H), 7.11-7.03(m,2H),6.57(dd,J=1.5Hz,5.2Hz,1H),6.54(m,1H), 4.78(bs,2H),3.92(s,3H) 20 Mass,m/e:285(M+,base) b) 3-(4-Fluorophenyl)-4-[(4-(2-methoxvpyridyl)l-5-(phenylacetyl amino)isoxazole In 5 mL of THF, 0.050 g of imidazole and 0.22 mL of DBU were 25 dissolved, to which 0.10 mL of phenylacetyl chloride was added dropwise under stirring and cooling with ice, followed by ten minutes' stirring at room temperature. Then a solution of 0.050 g of 5-amino- 3- (4-fluorophenyl) -4- [4- (2- methoxypyridyl)]isoxazole in 5 mL of THF was added dropwise, followed by 5 hours' stirring at room 30 temperature. Distilling the solvent off from the reaction solution under reduced pressure, water was added to the residue and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off under reduced pressure. The resultant residue was 35 purified on 10 g silica gel column chromatography (eluent, chloroform 88 -> chloroform: methanol = 60: 1) to provide 0.132 g (yield: 61%) of the title compound as colorless crystals. 1H-NMR(CDCl)6:8.05(d,J=5.4Hz,1H),7.40-7.36(m,5H), 5 7.30-7.26(m,1H),7.06-7.02(m,2H),6.45(dd,J=1.5Hz,5.2Hz,lH), 6.39(bs,1H),4.78(bs,2H),3.93(s,3H),3.77(s,2H) Mass,m/e:403(M+),9 1 (base) Example 188 10 3-(4-Fluorophenyl)-4-[4-(2-methoxypyridyl)]-5-[(2-chlorophenvl) acetylaminolisoxazole The title compound was synthesized in the manner similar to Example 187. 15 IH-NMR(CDCla)6:8.09-8.05(m,1H),7.45-7.23(m,7H), 7.08-7.02(m,2H),6.58-6.52(m,1H),6.47(bs,1H),3.93(s,3H), 3.88(s,2H) Mass,m/e:437(M+), 125(base) 20 Example 189 4- [4-(2-aminopyridyl)] -3-(4-fluorophenyl)-5-(phenylacetylamino) isoxazole a) 2-fl-(2,4-dimethylpyrrolyl)]-4-methylpyridine To 100 mL of a benzene solution containing 5.00 g of 25 2-amino-4-methylpyridine and 5.96 g of acetonylacetone, 3.20 mL of acetic acid was added and heated under reflux for 12 hours. Thereafter 2.98 g of acetonylacetone and 1.6 mL of acetic acid were added, followed by further 9 hours' heating under reflux. Then water-methanol was added to the reaction solution and stirred for an 30 hour at room temperature. The crystals precipitated were recovered by filtration and dried under reduced pressure to provide 6.24 g (yield: 73%) of the title compound as light brown crystal. 1H-NMR(CDCl 3 )6:8.44(d,J=5.1Hz, 1H),7.20-7.00(m,2H), 35 5.87(s,2H),2.42(s,3H),2.11(s,6H) 89 b) 2- [1- (2,5 -dimethylpyrrolyl)] -4-pyridylacetonitrile A mixture of 3.0 g of 2-[1-(2,4-dimethylpyrrolyl)] -4 methylpyridine and 8.3 g of t-butoxybisdimethylaminomethane was 5 stirred at 110*C for 4 hours. The reaction solution was cooled and from which the t-butoxybisdimethylaminomethane was distilled off under reduced pressure, to obtain blackish brown, oily residue. Ten (10) mL of water and 4.6 g of hydroxylamine-O-sulfonic acid were added to the residue and stirred at room temperature for an hour. 10 The reaction solution was rendered basic by addition of saturated aqueous sodium hydrogencarbonate solution under cooling with ice, and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. The resultant 15 residue was purified on 100 g silica gel column chromatography (eluent, chloroform: methanol = 100: 1) to provide 2.8 g (yield: 82%) of the title compound as pale yellow crystal. 1H-NMR(CDCl 3 )8:8.62(d,J=5. 1Hz, 1H),7.40-7.20(m,2H), 20 5.91(s,2H),3.84(s,2H),2.13(s,6H) c) 5-Amino-3-(4-fluorophenyl)-4-[4- [2- [1-(2,5-dimethylpyrrolyl)] pyridyl]]isoxazole In 10 mL of ethanol, 0.707 g of sodium ethoxide was dissolved, 25 and into which 10 mL of THF solution containing 1.1 g of 2-[1-(2,5-dimethylpyrrolyl)]-4-pyridylacetonitrile was dropped, followed by 30 minutes' stirring at room temperature. Then 10 mL of an ethanol solution containing 0.900 g of 4-fluorobenzhydroxymoyl chloride was added dropwise, followed by 2 hours' stirring at room 30 temperature. The solvent was distilled off under reduced pressure, and saturated aqueous ammonium chloride solution was added to the residue, followed by extraction with methylene chloride. The organic layer was dried over anhydrous magnesium chloride and from which the solvent was distilled off under reduced pressure. The resultant 35 residue was purified on 50 g silica gel column chromatography (eluent, 90 chloroform: methanol = 50: 1) to provide 0.96 g (yield: 53%) of the title compound as pale brown crystal. 1H-NMR(CDCla):8.55(d,J=5.0Hz, 1H),7.44-7.40(m,2H), 5 7.12-7.06(m,3H),6.89(d,J=1.5Hz, 1H),5.85(s,2H), 4.88(bs s,2H),2.01(s,6H) Mass,m/e:348(M+base) d) 3-(4-Fluorophenvl)-4-[4-[2-Il-(2,5-dimethvlpvrrolyl)]pyridylll-5 10 (phenylacetylamino)isoxazole To a mixture of 0.080 g of imidazole and 3 mL of THF, first 0.17 mL of DBU and then 0.15 mL of phenylacetyl chloride was added and stirred at room temperature for 15 minutes. Five (5) mL of THF solution containing 0.10 g of 5-amino-3-(4-fluorophenyl)-4- [4- [2-[1 15 (2,5-dimethylpyrrolyl)]pyridyl]]isoxazole and 0.17 mL of DBU was added, followed by 2 hours' stirring at room temperature. Water was added to the reaction solution which was then extracted with methylene chloride. The extract was washed first with saturated aqueous NaHCO3 solution and then with saturated brine, dried over 20 anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. The resultant residue was purified on 10 g silica gel column chromatography (eluent, chloroform -+ chloroform: methanol = 50: 1) and washed with ether to provide 0.037 g (yield: 27%) of the crystalline title compound. 25 1H-NMR(CDCl)8:8.49(dd,J=0.8Hz,5.1Hz,1H), 7.39-7.33(m,6H),7.23-7.21(m,2H),7.07-7.03(m,2H), 6.93(dd,J=1.5Hz,5.1Hz,1H),6.83(bs,1H), 5.86(s,2H),3.74(s,2H),2.00(s,6H) 30 Mass,m/e:466(M+),91(base) e) 4-[4-(2-Aminopyridyl)1-3-(4-fluorophenyl)- 5-(phenylacetyl amino)isoxazole A mixture of 0.032 g of 3-(4-fluorophenyl)-4-[4-[2- [1-(2,5 35 dimethylpyrrolyl)]pyridyl]]-5-(phenylacetylamino)isoxazole, 0.058 g of 91 hydroxylamine hydrochloride, 1 mL of ethanol and 1 mL of water was stirred at room temperature for 19 hours. The reaction solution was cooled, from which the solvent was distilled off under reduced pressure and water was added to the residue, followed by extraction 5 with chloroform. The chloroform extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and from which the solvent was distilled off under reduced pressure. The resultant residue was purified on 10 g silica gel column chromatography (eluent, chloroform -+ chloroform: methanol = 50 : 1) to provide 0.011 g (yield: 10 41%) of the crystalline title compound. 1H-NMR(CDCl 3 )S:7.93(d,J=5.4Hz,1H),7.42-7.35(m,5H), 7.29-7.26(m,3H),7.06-7.02(m,2H),6.20(dd,J=1.5Hz,5.4Hz,1H), 6.05(bs,1H),4.39(bs,2H),3.79(s,2H) 15 Mass,m/e:388(M+),91(base) In the following, the compounds of Examples 190 - 193 were synthesized in the manner similar to Example 189. 20 Example 190 4-[4-(2-Aminopyridyl)]-5-[2-(2-chlorophenvl)acetylamino]-3-(4 fluorophenvl)isoxazole 1H-NMR(CDCla)S:7.93(d,J=5.4Hz,1H),7.44-7.40(m,3H), 25 7.35-7.28(m,3H),7.26-23(m,1H),7.07-7.02(m,2H), 6.28(dd,J=1.5Hz,5.4Hz,1H),6.21(bs,1H),4.53(bs,2H), 3.89(s,2H) Mass,m/e:422(M+), 125(base) 30 Example 191 4-[4-(2-Aminopyridyl)I-5-[2-(2,6-dichlorophenyl)acetylaminol-3 (4-fluorophenyl)isoxazole 1H-NMR(DMSO-d 6 )8:11.03(bs, 1H),7.88(d,J=5.4Hz, 1H), 35 7.49-7.46(m,4H),7.36-7.28(m,3H),6.32(dd,J=1.5Hz,5.4Hz, 1H), 92 6.2 1(bs, 1H),5.93(bs,2H),4.04(s,2H) Mass,m/e:456(M+), 159(base) Example 192 5 4-[4-(2-Aminopyridyl)]-5-[2-(2,4-dichlorophenyl)acetylaminol-3 (4-fluorophenyl)isoxazole 1H-NMR(CDCl 3 )S:7.96(d,J=5.4Hz,1H),7.45-7.41(m,3H), 7.25(bs,3H),7.05(t,J=8.9Hz,2H),6.31(dd,J=1.5Hz,5.4Hz,1H), 10 6.22(bs,1H),4.48(bs,2H),3.86(s,2H) Mass,m/e:456(M+), 159(base) Example 193 4-[4-(2-Aminopyridyl)]-3-(4-fluorophenyl)-5-[2-methyl-2-phenyl 15 (acetylamino)]isoxazole 1H-NMR(CDCl 3 )S:7.87(d,J=5.4Hz,1H),7.41-7.27(m,8H), 7.04(t,J=8.9Hz,2H),6.13(d,J=5.4Hz,1H),5.96(bs,1H), 4.50(bs,2H),3.81-3.74(m,1H),1.57 and 1.55(s,3H) 20 Mass,m/e:402(M+), 105(base) Example 194 4-[4-(2-Dimethylaminopyridyl)]-3-(4-fluorophenyl)-5-(phenylacetyl amino)isoxazole 25 A mixture of 80 mg of 4-[4-(2-bromopyridyl)]-3-(4-fluoro phenyl)-5-(phenylacetylamino)isoxazole and 0.3 mL of HMPA was stirred at 200*C for 50 minutes. The solvent was distilled off from the reaction solution under reduced pressure. The resultant residue was purified on thin-layer chromatography (developer, chloroform: 30 methanol = 100 : 1) to provide 2 mg (yield: 3%) of the title compound. 1H-NMR(CDCl 3 )5: 8.05(d,J=5.7Hz, 1H),7.53-6.93(m, 10H),6.13-6.07(m,2H), 3.77(s,2H),2.95(s,6H) 35 Mass, m/e:416(M+),91(base) 93 Example 195 4-[4-(2-Dimethylaminopyridyl)]-3-(4-fluorophenyl)-5-[2-methyl-2 phenvl(acetylamino)]isoxazole 5 The title compound was synthesized in the manner similar to Example 194. 1H-NMR(CDCl 3 )6:8.01(dd,J=0.8Hz,5.OHz,1H), 7.45-7.40(m,2H),7.37-7.31(m,4H),7.26-7.22(m,2H), 10 7.05-7.00(m,2H),6.06(bs,1H),6.03(dd,J=1.2Hz,5.OHz,1H), 3.79(bs,1H),2.93(s,6H),1.54(d,J=7.3Hz,3H) Mass, m/e:430(M+),105(base) Example 196 15 5-[(2-Chlorophenyl)acetylamino]-3-(4-fluorophenyl)-4-[4-(2 methylpyridyl)]isoxazole a) 4-Chloromethyl-2-methylpyridine Into 100 mL of methylene chloride solution containing 2.16 g o 4-(2-methylpyridyl)methanol (cf. PCT International Publication 20 W098/21210 Pamphlet), 23 mL of thionyl chloride was dropped at room temperature, followed by 20 hours' stirring at room temperature. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was extracted with methylene chloride, after addition of saturated aqueous NaHCO 3 solution. The 25 methylene chloride extract was dried over anhydrous magnesium sulfate, and from which the solvent was distilled off under reduced pressure to provide 2.46 g (yield: 100%) of brown crystalline title compound. 30 1H-NMR(CDCl 3 )8:8.45(d,J=5.OHz,1H),7.31(s,lH), 7.25(d,J=5.OHz,1H),4.74(s,2H),2.48(s,3H) Mass,m/e: 141(M+,base) b) 4-(2-Methylpyridyl)acetonitrile 35 To 10 mL of DMSO solution containing 1.7 g of sodium cyanide, 94 3 mL of DMSO solution containing 2.46 g of 4-chloromethyl-2 methylpyridine was added under cooling with ice, and stirred at room temperature for 3 hours. After addition of water, the reaction solution was extracted with ethyl acetate. The ethyl acetate extract 5 was washed with water, dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation to provide 1.86 g (yield: 80%) of the title compound which was a reddish brown, oily substance. 10 1H-NMR(CDCl3):8.43(d,J=5.OHz,1H),7.22(s,1H), 7.16(d,J=5.OHz,1H),4.08(s,2H),2.47(s,3H) Mass,m/e: 132(M+,base) c) 5-Amino- 3-(4- fluorophenyl) -4- [4- (2-methylpyridyl) isoxazole 15 To 3.3 mL of 28% sodium methoxide-methanol solution, 15 mL of methanol and 15 mL of THF solution containing 1.86 g of 4-(2-methylpyridyl)acetonitrile were added and stirred at room temperature for 30 minutes. Then 15 mL of a methanol solution containing 2.9 g of 4-fluorobenzhydroxymoyl chloride was added, 20 followed by 30 minutes' stirring at room temperature. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was extracted with a mixed solvent of chloroform: methanol = 1 : 1, after addition of water. The organic layer was dried over anhydrous magnesium sulfate and removed of the solvent by 25 reduced pressure distillation. The resultant residue was purified on 100 g silica gel column chromatography (eluent, chloroform: methanol = 100 : 1 -> 20: 1) to provide 0.955 g (yield: 25%) of the title compound as reddish brown crystals. 30 1H-NMR(CDCl 3 )6:8.41(d,J=5.2Hz,1H), 7.32(dd,J=5.4Hz,8.6Hz,2H),7.05(t,J=8.6Hz,2H), 6.93(bs,1H),6.83(dd,J=1.5Hz,5.2Hz,1H),4.80(bs,2H), 2.50(s,3H) Mass,m/e:269(M+,base) 35 95 d) 5-[(2-Chlorophenyl)acetylaminol-3-(4-fluorophenyl)-4-[4-(2 methylpyridyl)lisoxazole To 5 mL of THF solution containing 0.21 g of 2-chlorophenyl acetic acid, 0.2 g of CDI was added and stirred at room temperature 5 for an hour. Then 10 mL of THF solution containing 0.1 g of 5-amino- 3-(4-fluorophenyl) -4- [4- (2- methylpyridyl)] isoxazole and 0.4 mL of DBU were added and stirred for 12 hours. After distilling the solvent off from the reaction solution under reduced pressure, water was added to the residue, followed by extraction with ethyl acetate. 10 The ethyl acetate extract was dried over anhydrous magnesium sulfate and from which the solvent was distilled off under reduced pressure. The resultant residue was purified on 15 g silica gel column chromatography (eluent, chloroform: methanol = 100 : 1) to provide 0.12 g (yield: 77%) of the colorless crystalline title compound. 15 1H-NMR(CDCl 3 )5:8.38(d,J=5.2Hz,1H),7.55(bs,1H), 7.44-7.42(m,1H),7.38-7.28(m,5H),7.04(t,J=8.4Hz,2H), 6.87(s,1H),6.77(dd,J=1.lHz,5.2Hz,1H),3.87(s,2H), 2.47(s,3H) 20 Mass,m/e:421(M+), 125(base) Example 197 3-(4-Fluorophenyl)-4-[4-(2-methylpyridvl)]-5-(3-phenylpropionyl amino)isoxazole 25 The title compound was synthesized in the manner similar to Example 196. 1H-NMR(CDCl 3 )6:8.38(d,J=5.OHz,1H),7.66(bs,1H), 7.35(dd,J=5.3Hz,8.6Hz,2H),7.29-7.16(m,5H), 30 7.03(t,J=8.6Hz,2H),6.86(s,1H),6.78(d,J=5.OHz,1H), 3.00(t,J=7.3Hz,2H),2.75(t,J=7.3Hz,2H),2.46(s,3H) Mass,m/e:40 1(M+),9 1(base) Example 198 35 4-[4-(2,6-Dimethylpyridyl)]-3-(4-fluorophenyl)-5-phenylacetylamino- 96 isoxazole a) 4- Chloromethyl-2,6 -dimethylpyridine To 45 mL of methylene chloride solution containing 1.0 g of 4-(2,6 -dimethylpyridyl)methanol (cf. PCT International Publication 5 W098/21210 Pamphlet), thionyl chloride was added dropwise at room temperature, followed by 21 hours' stirring. The solvent was distilled off from the reaction solution under reduced pressure, and to the residue saturated aqueous NaHCO3 solution was added, followed by extraction with methylene chloride. The organic layer was dried 10 over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation to provide 1.0 g (yield: 88%) of the title compound as a yellow oily substance. 1H-NMR(CDCl 3 )6:6.95(s,2H),4.43(s,2H),2.50(s,6H) 15 Mass,m/e:155(M+,base) b) 4-(2,6-Dimethylpyridvl)acetonitrile To 4 mL of DMSO solution containing 0.63 g of sodium cyanide, 1 mL of DMSO solution containing 1.00 g of 20 4-chloromethyl-2,6-dimethylpyridine was added under cooling with ice, and stirred at room temperature for 2 hours. Water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried over anhydrous magnesium sulfate and removed of the solvent by reduced 25 pressure distillation to provide 0.86 g (yield: 92%) of the title compound as a reddish brown, oily substance. 1H-NMR(CDCl 3 )8:7.01(s,2H),4.02(s,2H),2.49(s,6H) Mass,m/e: 146(M+,base) 30 c) 5-Amino- 4- [4- (2,6-dimethylpyridvl) -3 -(4-fluorophenyl)isoxazole To 1.4 mL of 28% sodium methoxide-methanol solution, 7 mL of THF solution containing 0.86 g of 4-(2,6-dimethylpyridyl) acetonitrile was added and stirred at room temperature for 20 35 minutes. Then 7 mL of methanol solution containing 1.23 g of 97 4-fluorobenzhydroxymoyl chloride was added and stirred at room temperature for 13 hours. The solvent was distilled off from the reaction solution under reduced pressure, and water was added to the residue, followed by extraction with chloroform. The organic layer 5 was dried over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The resultant residue was purified on 80 g silica gel column chromatography (eluent, chloroform: methanol = 100 : 1 -+ 40 : 1) to provide 0.425 g (yield: 25%) of reddish brown, crystalline title compound. 10 1H-NMR(CDCl)8:7.41(dd,J=5.4Hz,8.4Hz,2H), 7.04(t,J=8.4Hz,2H),6.72(s,2H),4.78(bs,2H),2.45(s,6H) Mass,m/e:283(M+,base) 15 d) 4-[4-(2,6-Dimethylpyridyl)]-3-(4-fluorophenyl)-5-phenylacetyl aminoisoxazole To 8 mL of THF solution containing 90 mg of imidazole and 0.4 mL of DBU, 0.16 mL of phenylacetyl chloride was added under cooling with ice, and stirred for an hour at room temperature. Then 8 mL of 20 THF solution containing 0.1 g of 5-amino-4-[4-(2,6-dimethylpyridyl)] 3-(4-fluorophenyl)isoxazole was added, followed by 3 days' stirring. The solvent was distilled off from the reaction solution under reduced pressure, and to the resultant residue water was added, followed by extraction with ethyl acetate. The ethyl acetate extract was dried 25 over anhydrous magnesium sulfate and removed of the solvent by reduced pressure distillation. The resultant residue was purified on 15 g silica gel column chromatography (eluent, chloroform: methanol = 100 : 1) and then on thin-layer chromatography (developer, chloroform: methanol = 100: 1) to provide 53 mg (yield: 37%) of yellow 30 crystalline title compound, 1H-NMR(CDCl3)5:7.38-7.23(m,8H),7.03(t,J=8.4Hz,2H), 6.56(s,2H),3.76(s,2H),2.42(s,6H) Mass,m/e:40 1(M+),9 1 (base) 35 98 In the following, the compounds of Examples 199 - 200 were synthesized in the manner similar to Example 198. Example 199 5 5-[(2-Chlorophenvl)acetylamino]-4-[4-(2,6-dimethylpyridyl)]-3 (4-fluorophenvl)isoxazole 1H-NMR(DMSO-d 6 )5:11.02(bs,1H),7.45-7.42(m,3H), 7.39-7.36(s,1H),7.33-7.27(m,4H),6.82(s,2H),3.86(s,2H), 10 2.35(s,6H) Mass,m/e:435(M+), 125(base) Example 200 4-[4-(2,6-Dimethylpyridyl)1-3-(4-fluorophenyl)-5-(3-phenylpropionvl 15 amino)isoxazole 1H-NMR(CDCl 3 )8:7.40(bs,1H),7.37(dd,J=5.3Hz,8.8Hz,2H), 7.29-7.27(m,2H),7.22-7.16(m,3H),7.03(t,J=8.8Hz,2H), 6.69(s,2H),3.00(t,J=7.3Hz,2H),2.76(m,2H),2.46(s,6H) 20 Mass,m/e:415(M+),91(base) Formulation Example 1 Tablet: mg/tablet 25 Active ingredient 5.0 Starch 10.0 Lactose 73.0 Carboxymethyl cellulose calcium 10.0 Talc 1.0 30 Magnesium stearate 1.0 100.0 The active ingredient is pulverized to a grain size not greater than 70 ptm, and to which starch, lactose and carboxymethyl cellulose 35 calcium are added and thoroughly mixed. Ten (10)% starch paste is 99 added to the mixture, mixed by stirring and granulated. After drying, the granules are dressed to around 1000 pm in particle size. Mixing talc and magnesium stearate therewith, the blend is tabletted.

Claims

1. Isoxazole derivatives which are represented by a formula (I) ( I) RO R3 N in the formula, R' and R 2 each independently stands for hydrogen, halogen, lower alkyl, lower alkoxy, amino, lower alkylamino, di-lower alkyl amino, phenyl-lower alkylamino, acylamino, lower alkylthio or lower alkylsulfinyl, R 3 stands for naphthyl, optionally lower alkyl-substituted heteroaryl or a group represented by the following formula (A) xi 2_( A) X 3 wherein X1, X 2 and X 3 each independently stands for hydrogen, halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, hydroxyl, lower alkanoyl, lower haloalkanoyl or phenyl; or X 1 and X 2 together stand for lower alkylenedioxy group, R 4 stands for hydrogen or lower alkyl, R 5 stands for phenyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl or isoxazolyl, which may be optionally substituted with 1 - 3 substituents selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, hydroxyl, lower alkanoyl, lower haloalkanoyl, lower alkylthiocarbonyl, lower haloalkylthio carbonyl, amino, lower alkylamino, di-lower alkylamino and nitro, Y stands for -(CH 2 )n-, -CO-, -CH(CH 3 )-, -C(CH 3 ) 2 -, -0-, -NH- or ___ , wherein n is an integer of 1 - 3, 101 with the proviso that, where both of R1 and R 2 stand for hydrogen and R 3 stands for the group of the formula (A) and two of XI, X 2 and X 3 stand for hydrogen, the remaining one of X1, X 2 and X 3 is a group other than hydrogen atom or halogen atom, or pharmaceutically acceptable salts thereof.

2. Isoxazole derivatives or their pharmaceutically acceptable salts according to Claim 1, in which RI and R 2 each independently stands for hydrogen, amino, lower alkylamino or di-lower alkylamine.

3. Isoxazole derivatives or their pharmaceutically acceptable salts according to Claim 1 or 2, in which R 3 stands for a group of the following formula (A) x 3

4. Isoxazole derivatives or their pharmaceutically acceptable salts according to Claim 3, in which X1, X 2 and X 3 each independently stands for hydrogen, halogen, lower alkyl or lower alkoxy.

5. Isoxazole derivatives or their pharmaceutically acceptable salts according to any one of Claims 1 - 4, in which R 4 stands for hydrogen.

6. Isoxazole derivatives or their pharmaceutically acceptable salts according to any one of Claims 1 - 5, in which R 5 stands for phenyl which is optionally substituted with 1 - 3 substituents selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, hydroxyl, lower alkanoyl, lower haloalkanoyl, lower alkylthiocarbonyl, lower haloalkylthiocarbonyl, amino, lower alkylamino, di-lower alkylamino and nitro.

7. Isoxazole derivatives or their pharmaceutically acceptable 102 salts according to Claim 6, in which R 5 stands for phenyl which is optionally substituted with 1 or 2 substituents selected from halogen and lower alkyl.

8. Isoxazole derivatives or their pharmaceutically acceptable salts according to Claim 7, in which R5 is phenyl, 2-halophenyl, 2,6-dihalophenyl, 2-lower alkylphenyl, 3-lower alkylphenyl or 2,5-di-lower alkylphenyl.

9. Isoxazole derivatives or their pharmaceutically acceptable salts according to any one of Claims 1 - 8, in which Y stands for -CH2- or -CH 2 CH 2 -.

10. Isoxazole derivatives or their pharmaceutically acceptable salts which are selected from the group consisting of 3-(3-methylphenyl)-5-(3-phenylpropionylamino)-4-(4-pyridyl) isoxazole, 3-(3-methylphenyl)-5-[(2-methylphenyl) propionylaminol-4 (4-pyridyl)isoxazole, 5-[(3-chlorophenyl)propionylamino]-3-(2-fluoro-5-methyl phenyl)-4-(4-pyridyl)isoxazole, 3-(4-fluoro-3-methylphenyl)-5-(phenylacetylamino)-4 (4-pyridyl)isoxazole, 5-[(2-chlorophenyl)acetylamino]-3-(4-fluoro-3-methylphenyl)-4 (4-pyridyl)isoxazole, and 3-(4-fluoro-3-methylphenyl)-5-(3-phenylpropionylamino)-4 (4-pyridyl)isoxazole.

11. p38MAPkinase inhibitors characterized by containing the isoxazole derivatives or their pharmaceutically acceptable salts which are described in any one of Claims 1 - 10, as the active ingredient.

12. Medicines which contain the isoxazole derivatives or their pharmaceutically acceptable salts which are described in any one of Claims 1 - 10. 103

13. Pharmaceutical compositions which contain an effective amount of the isoxazole derivatives or their pharmaceutically acceptable salts which are described in any one of Claims 1 - 10, together with non-toxic excipients.

14. Treating agents of Tumor Necrosis Factor-a related disease, Interleukin- 1-related disease, Interleukin-6-related disease, Interlekin-8 -related disease and Cyclooxygenase-II -related disease, characterized by containing as the active ingredient the isoxazole derivatives or their pharmaceutically acceptable salts which are described in any one of Claims 1 - 10.

15. Treating agents according to Claim 14, in which the Tumor Necrosis Factor-a related disease, Interleukin-1-related disease, Interleukin-6-related disease, Interlekin-8-related disease and Cyclooxygenase-II-related disease are acute inflammation, chronic inflammation, rheumatoid arthritis, osteoarthritis, gout, inflammatory bowel disease, Crohn's disease, ulcerative colitis, gastritis, colonic polyposis, large bowel cancer, colon cancer, asthma, bronchitis, bronchial asthma, allergic rhinitis, ARDS, chronic obstructive pulmonary disease, pulmonary fibrosis, congestive heart disease, ischemic heart disease, myocardial infarction, arteriosclerosis, hypertension, angina, Alzheimer's disease, reperfusion injury, angiitis, cerebrovascular disease, meningitis, multiple sclerosis, osteoporosis, bony sclerosis, Behcet's Syndrome, bone metastasis, multiple myeloma, acute infectious disease, septic shock, sepsis, toxic-shock syndrome, tuberculosis, DIC, psoriasis, atopic dermatitis, cirrhosis, renal fibrosis, cachexia, AIDS, cancer, autoimmune disease, diabetes, Castleman's disease, .mesangial nephritis, endometriosis and preterm delivery.

16. Method for treating Tumor Necrosis Factor-a related disease, Interleukin- 1-related disease, Interleukin-6-related disease, Interlekin-8-related disease and Cyclooxygenase-II-related disease, 104 characterized by administering the isoxazole derivatives or pharmaceutically acceptable salts thereof which are described in any one of Claims 1 - 10 to the patients whose treatment is necessary.